Florencio Zaragoza Dörwald Lead Optimization for Medicinal Chemists

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Florencio Zaragoza Dorwald¨

Lead Optimization for Medicinal Chemists Related Titles

Smith, D. A., Allerton, C., Kalgutkar, A. S., Curry, S. H., Whelpton, R. van de Waterbeemd, H., Walker, D. K. Drug Disposition and Pharmacokinetics and Metabolism Pharmacokinetics in Drug Design From Principles to Applications

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2009 ISBN: 978-3-527-32331-9 Florencio Zaragoza Dorwald¨

Lead Optimization for Medicinal Chemists

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Contents

Introduction XIII Glossary and Abbreviations XV

Part I Introduction 1

1 The Drug Discovery Process 3 1.1 Pharmacokinetics–Structure Relationship 5 1.2 The Future of Small-Molecule Drugs 9 References 11

2 Lead Optimization 13 2.1 What Limits/Reduces Oral Bioavailability? 14 2.2 What Limits/Reduces Plasma Half-Life? 15 2.3 How to Improve bbb-Penetration? 16 2.4 How to Avoid CYP Inhibition/Induction? 16 2.5 How to Avoid Interaction with the Human Ether-a-go-go-Related` Gene (hERG)? 17 2.6 How to Prevent Toxicity? 17 2.7 Examples of PK-Optimization in Animals 20 2.7.1 Dihydroorotate Dehydrogenase Inhibitors 20 2.7.2 Matrix Metalloproteinase Inhibitors 21 2.7.3 Antibacterial Aminobenzenesulfonamides 21 2.7.4 Tyrosine Kinase Inhibitors 22 2.7.5 5-HT1A Agonists 23 2.7.6 Dipeptidyl Peptidase IV Inhibitors; Structural Variations of Sitagliptin 23 2.7.7 P-Selectin Inhibitors 24 2.7.8 β3-Adrenergic Agonists 24 2.7.9 Vanilloid-1 Antagonists 25 2.7.10 HIV Protease Inhibitors 25 2.7.11 Matrix Metalloproteinase Inhibitors (Tested in Rats) 26 2.7.12 HIV Integrase Inhibitors 26 2.7.13 Dopamine D3 Antagonists 27 2.7.14 Inhibitors of Soluble Epoxide Hydrolase (Tested in Mice, po) 28 VI Contents

2.7.15 Melanin-Concentrating Hormone Receptor-1 Antagonists 29 References 29

Part II The Pharmacokinetic Properties of Compound Classes 33

3Alkanes35 3.1 Metabolism 36 References 39

4 Alkenes and Alkynes 40 4.1 Metabolism 40 References 44

5 Arenes 45 5.1 Metabolism 45

6Halides49 6.1 Fluorine 49 6.2 Chlorine 51 6.3 Bromine 53 6.4 Iodine 53 6.5 Alkylating Agents 54 Reference 55

7 Azides 58

8 Nitro Compounds 59 8.1 Metabolism 60

9 Azo Compounds 62

10 Triazenes 64

11 Nitrates and Nitrites 66 Further Reading 67

12 N-Nitroso Compounds 68

13 N-Oxides 70

14 Alcohols 71 14.1 Metabolism 72 Contents VII

15 Phenols 82 References 84

16 Ethers 91 16.1 Metabolism 92 Reference 93

17 Epoxides 96

18 Peroxides 97

19 Thiols 98

20 Thioethers 100 20.1 Metabolism 101 Reference 103

21 Sulfoxides 104

22 Sulfones 106

23 Aliphatic Amines 107 23.1 Basicity 110 23.2 Metabolism 110 23.3 Rates of N-Dealkylation 112 Reference 114

24 Quaternary Ammonium Salts 118 Reference 119

25 Amidines 120 Reference 121

26 Guanidines, Acylguanidines, and Biguanides 122 26.1 Acylguanidines 123 26.2 Biguanides 123 Reference 124

27 Anilines 133 27.1 Metabolism 135

28 Hydrazines, Acylhydrazines, and Hydrazones 137 VIII Contents

29 Aldehydes 138

30 Ketones 139

31 Carboxylic Acids 144 31.1 Metabolism 145 31.2 Bioisosteres of Carboxylic Acids 146 31.3 Amino Carboxylic Acids, N-Acyl Amino Acids, and Related Compounds 147 References 148

32 Carboxylic Esters 164 Reference 165

33 Amides 166

34 Lactams and Imides 172 34.1 Pyrazolone Antipyretics 172 34.2 Five-Membered Lactams as Nootropics 173 References 174

35 Nitriles 184 References 185

36 Carbonates 186

37 Carbamates 187 37.1 Carbamates as Hypnotics 188 References 189

38 Ureas 192 Reference 193

39 Thiocarbonyl Compounds 201

40 Sulfonic Acids 203

41 Sulfonic Esters 206

42 Sulfates and Sulfamic Acids 207

43 Phosphonic Acids 209 Contents IX

44 Phosphoric Acid Derivatives 213

45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds 215 Reference 216

46 Arylalkylamines 225 46.1 Antihistaminics: History 225 Reference 226

47 Phenethylamines (2-Phenylethylamines) 267 47.1 Biological Activity of Phenethylamines 267 47.2 Metabolism 268 47.3 Tetrahydroisochinolines and Related Compounds 269 Further Reading 270

48 Aminoalkylindoles and Indole Alkaloids 291 Reference 291

49 Phenothiazines 301 49.1 Metabolism 302 References 302

50 Dibenzazepines and Related Tricyclic Compounds 310

51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’) 320 51.1 Metabolism 320

52 Opiates 329 Reference 329

53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils) 335 Reference 336

54 Anilides and Amides of Glycine 341

55 Peptides, Peptidomimetics, and Related Oligoamides 347 55.1 Peptidomimetics 348 55.2 Thrombin Inhibitors and Related Compounds 349 References 350 X Contents

56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas 365 References 365

57 Imidazoles 377 References 378

58 Triazoles 387

59 Pyridines, Pyrimidines, and Related Compounds 393 59.1 Proton Pump Inhibitors 396 References 397

60 Quinolines 412 60.1 Tecans 415 60.2 Quinazolines 415 References 416

61 Nucleoside Analogs 428 Reference 428

62 Dihydropyridines 446

63 Arenesulfonamides 450 63.1 Antibacterials 450 63.2 Diuretics 450 Reference 451

64 Sulfonylureas 462

65 Benzodiazepines 466 Reference 467

66 Steroids 477 References 478

67 Anthracyclines 492

68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDS) 497 68.1 Salicylates 497 References 498 Contents XI

69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 514

70 β-Lactams 522 70.1 Cephalosporins 523 Reference 523

71 Prostaglandin Analogs 538

72 Sartans 543 Reference 544

73 Statins 548

74 Folic Acid Analogs (Antifolates) 551

75 Taxanes 554 Reference 554

76 Macrocyclic Compounds 557 Reference 557

Index 567 XIII

Introduction

The aim of this book is to provide medicinal chemists with a guide to the effect of structural modifications and functional groups on the pharmacokinetic (PK) properties of compounds, illustrated by a full collection of PK data. How does the plasma half-life and oral bioavailability change on small structural modifications? Which structural elements are allowed for a drug, and which are interchangeable, without significantly altering the PK properties? How can the oral bioavailability and half-life of a lead be increased? Questions of this type, critical to every small molecule drug development program, are addressed herein. The tables contain most drugs for which human PK data have been reported. Some compounds in clinical development or with animal PK data only have also been included. The compounds listed include currently available drugs, withdrawn drugs, and compounds that failed during clinical trials. Compounds are arranged by keeping structurally closely related drugs together, to show variations of PK properties on minimal structural modification. This kind of information should be particularly valuable for medicinal chemists in their endeavor to improve the PK of their leads. PK data are no natural constants inherent to a compound, such as its melting point or density, but depend on the sex, age, and condition of the patient, his diet, the dose of the drug, and the hour at which the measurement is performed. In a typical study with 5–10 healthy volunteers, half-life and oral bioavailability may show strong interindividual variations. Even for a single patient, PK properties of a drug will change with each new dosing. Thus, the establishment of a true PK SAR (structure activity relationship) for drugs would require PK data obtained from huge groups of people. Understandably, such information is not available. The accuracy of compound quantization in plasma and thus the quality of PK data has increased dramatically in recent years. Moreover, a more complete PK profile is requested today by the regulatory agencies than in the past. Therefore, older PK data is usually less accurate and less complete than more recent data. Because PK is highly variable between individuals, even high-quality data must be used with caution by physicians. Also, medicinal chemists should keep in mind that (i) reported PK values are always inaccurate and (ii) vary strongly between patients. Nevertheless, short of anything better, the values reported herein should give XIV Introduction

chemists an estimate of the PK properties of compound classes and a knowledge of how structural modiﬁcations will probably affect PK. The PK data and other information presented herein was collected from various sources:

1) Books: Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 9th edn, Hardman, J. G.; Limbird, L. E. eds., McGraw-Hill, 1996. Forth, W.; Henschler, D.; Rummel, W. Pharmakologie und Toxikologie. Mannheim: B.I. Wissenschaftsverlag, 1987. Jack, D. B. Handbook of Clinical Pharmacokinetic Data. Macmillan Publishers Ltd, 1992. Bochner, F.; Carruthers, G.; Kamp- mann, J.; Steiner, J. Handbook of Clinical Pharmacology, 2nd edn, Boston, Toronto: Little, Brown & Co, 1983; 2) Peer-reviewed publications, for example, Obach, R. S.; Lombardo, F.; Waters, N. J. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab. Dispos., 2008, 36, 1385–1405; Smith, D. A.; Jones, B. C.; Walker, D. K. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Medicinal Research Reviews, 1996, 16, 243–266; 3) Public online databases: EMA-ﬁlings (www.ema.europa.eu), the swiss Arzneimittel Kompendium (www.kompendium.ch), the drug bank (www. drugbank.ca), banque des donnees´ automatisee´ sur les medicaments´ (www.biam2.org), clinical drug use (www.clinicaldruguse.com), PharmGKB (www.pharmgkb.org), medsafe (www.medsafe.govt.nz).

On minor discrepancies between sources, the mean value was calculated. In case of major inconsistencies, preference was given to newer data. Clearance (CL) is reported as given in the literature; its consistency with the reported values of t1/2 and V was not veriﬁed. The values for polar surface area (PSA) and log P were calculated with ACD/Labs (Advanced Chemistry Development), Version 11.02 (uncharged compounds), or with Molinspiration Cheminformatics (www.molinspiration.com) (charged compounds). The historical background of many drugs and therapeutic strategies was gathered from the books cited above, from peer-reviewed articles, and from the excellent assays of Walter Sneader, Professor at the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow, Scotland. XV

Glossary and Abbreviations

ACE angiotensin converting enzyme ADME(T) absorbtion, distribution, metabolism, excretion, (toxicity) ADP adenosine diphosphate AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, a glutamate receptor ATP adenosine triphosphate AUC area under the curve; area under a plot of the concentration of the drug in plasma as function of time AUMC area under the ﬁrst moment of the concentration–time curve bbb blood–brain barrier BCL B-cell lymphoma BCNU N,N-bis(2-chloroethyl)nitrosourea, carmustine bp boiling point CDK cyclin-dependent kinases CETP cholesteryl ester transfer protein CCK cholecystokinin CETP cholesteryl ester transfer protein CGRP calcitonin-gene-related peptide CL clearance in ml min−1 kg−1 = dose/AUC; amount of plasma that is freed of the drug in a given time; CL = ln 2 × (V/t1/2) CNDAC 1-(2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl)cytosine CNS central nervous system COMT catechol-O-methyltransferase COX cyclooxygenase, enzyme involved in the conversion of arachidonic acid into prostaglandines CPIB p-chlorophenoxyisobutyric acid CYP cytochrome P450, group of hepatic enzymes that mediate oxidative metabolism DMPK drug metabolism and pharmacokinetics DPPIV dipeptidylpeptidase IV EMA European Medicines Agency F oral bioavailability; AUC (oral dose)/AUC (iv dose) FDA Food and Drug Administration GABA γ-aminobutyric acid, central neurotransmitter GI gastrointestinal XVI Glossary and Abbreviations

GLP-1 glucagon-like peptide 1 GnRH gonadotropin-releasing hormone, also called LHRH GPCR G-protein coupled receptor HCV hepatitis C virus hERG human ether-a-go-go` related gene HIV human immunodeficiency virus HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase, enzyme involved in reductase the biosynthesis of cholesterol 5-HT 5-hydroxytryptamine, serotonin im intramuscular ip intraperitoneal iv intravenous LH luteinizing hormone LHRH luteinizing-hormone-releasing hormone, also called GnRH logP log of partition coefficient of drug in a two-phase system octanol/water logP log P (octanol/water) − log P (cyclohexane/water) MAO monoamine oxidase MAP mitogen-activated protein MEK mitogen-activated protein kinase kinase mp melting point MRT mean residence time = AUMC/AUC Mwt molecular weight nd not determined NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NK neurokinin NMDA N-methyl D-aspartic acid NSAID nonsteroidal antiinflammatory drug PARP poly(ADP-ribose)polymerase pb extent to which drug is bound to plasma proteins PDE phosphodiesterase P-gp P-glycoprotein, a 170 kDa protein encoded by the multidrug resistance gene 1, which pumps drugs out of the resistant cells PK pharmacokinetic(s) po per os, oral PSA polar surface area PPAR-γ peroxisome-proliferator-activated receptor γ QT interval time for both the ventricular depolarization and repolarization R&D research and development SAR structure activity relationship sc subcutaneous SSRI selective serotonin reuptake inhibitor t1/2 plasma half-life of unchanged drug after oral administration to humans ur fraction of orally dosed drug being excreted unchanged in urine V volume of distribution = MRT × CL VEGF vascular endothelial growth factor 1

Part I Introduction

1 The Drug Discovery Process

Drugs are compounds that interact selectively with certain proteins in the human body and, thereby, suppress or activate biochemical pathways or signal transmission. Although the structures of modern drugs hardly allow to guess their origins, these were mostly natural products, discovered empirically, and used for centuries [1]. While synthesizing and evaluating new structural analogs of known hormones or natural drugs, new therapeutic applications often emerged. A fruitful starting point for the development of new drugs has in fact often been an old drug [2]. Illustrative examples of ‘‘drug evolution’’ are shown in Scheme 1.1.

OH OH H H HO N HO N

HO OH Adrenaline (natural neurotransmitter) Terbutaline α- +β-adrenergic agonist β-adrenergic agonist increases blood pressure and heart rate antiasthmatic

O OH H O N NC OH O O N H2N

Atenolol Cromakalim β-adrenergic antagonist potassium channel opener antihypertensive antihypertensive

Scheme 1.1 Examples of the development of new drugs from old drugs.

N N H HO N HN MeO N

N Cl N S Quinine (alkaloid of Chinchona) Chloroquine Promethazine antimalarial antimalarial antihistaminic

synthetic intermediate N O N MeO CO H 2 Cl N

N Cl N N H H Cl S Thalline weak antibacterial Chlorpheniramine Chlorpromazine antipyretic antihistaminic antipsychotic

failed quinolone antibacterials synthesis O N O O N N N N N N N O O

Phenazone Phenylbutazone Apazone antipyretic antipyretic antipyretic

Scheme 1.1 (Continued).

To initiate a drug discovery program with hormones, natural products, or old drugs as leads has a number of advantages: the biochemical concept is already proven (the compound ‘‘works’’), the target is ‘‘druggable,’’ and, importantly, the lead structure has acceptable or at least promising PK/ADME (pharmacokinetics/ absorption, distribution, metabolism, and excretion) properties; otherwise, it would not work. High-throughput screening of compound collections only rarely provides leads for new drugs [3]. Notable exceptions include the dihydropyridine calcium channel blockers, benzodiazepines, and sulfonamide antibacterials. These important drug classes resulted from testing drug-unrelated chemicals. New proteins are constantly being discovered, and many of them are potential targets for therapeutic intervention. It must be kept in mind, though, that only few drugs have been successfully developed from scratch, starting with a biochemical hypothesis. The odds for succeeding are higher with a lead that works in vivo or by optimizing or exploiting a side effect of an old drug. 1.1 Pharmacokinetics–Structure Relationship 5

Today, the development of a new drug usually comprises the following stages: 1) Discovery A target protein is selected, for example a receptor or an enzyme. If no lead structure is available, high-throughput screening of suitable, leadlike compounds may yield some weak ligands (hits). Systematic structural modification of these, supported by in vitro assays, may provide a lead, that is, a compound with an unambiguous dose–response relationship at the target protein. Further structural modifications aim at improving potency at the target, selectivity (low affinity to other proteins), water solubility, pharmacokinetics (PK, oral bioavailability, half-life, CNS penetration, etc.), therapeutic index (LD50/ED50), and general ADMET properties (absorption, distribution, metabolism, excretion, and toxicity). In addition to in vitro assays, the medicinal chemist will need guidance by more time- and compound- consuming in vivo pharmacology. 2) Preclinical development Once a development candidate has been chosen, the following steps will be initiated: chemical scale-up of the selected compound, formulation, stability studies, more detailed metabolic, toxicological, and PK studies (only in animals, typically rodents, dogs, pigs, or primates). 3) Clinical development

Phase I Healthy volunteers; determination of the suitable dose for humans Phase II First studies with a small group of patients Phase III Extended clinical trials

Thus, the fateful selection of a development candidate, which will either fail or succeed during the expensive preclinical or clinical development, is already taken in the discovery phase. Success in drug development is, therefore, primarily dependent on the medicinal chemist, on his ability to design and prepare the compound with the desired biological properties. No matter how hardworking and talented the members of the preclinical and clinical development team are, if the medicinal chemist has not delivered the right compound, the whole project will fail. And the later the recognition of the failure, the larger the costs. Thus, pharmaceutical companies should allocate signiﬁcant resources to the hiring and training of their medicinal chemists.

1.1 Pharmacokinetics–Structure Relationship

During the discovery phase of a new drug, two different, mutually independent sets of properties of the compound must be optimized: (i) potency and selectivity at the 6 1 The Drug Discovery Process

target protein and (ii) ADME and toxicity. The most critical ADME/PK parameters are as follows:

• Plasma half-life (t1/2): The time required for the plasma concentration of a drug to drop by 50%. A constant half-life means that the rate of elimination of a drug is a linear function of its concentration (first order kinetics). This is never exactly the case, and t1/2 will usually increase as the concentration of the drug declines. • Oral bioavailability (F): The fraction of a drug that reaches systemic circulation after oral dosing. Oral bioavailability is determined by dividing the area under the curve (AUC) for an oral dose by the AUC of the same dose given intravenously. AlowF means that either the drug is not absorbed from the gastrointestinal (GI) tract or that it undergoes extensive first-pass metabolism in the liver. • Plasma protein binding (pb): Hydrophobic compounds will bind unspecifically to any hydrophobic site of a protein. For this reason, high-throughput screening often yields hydrophobic hits (which are difficult to optimize and should be abandoned). Plasma proteins, such as albumin or α-glycoproteins, may also bind to drugs and thereby reduce their free fraction in plasma, their renal excretion, their ability to cross membranes (also the blood–brain barrier (bbb)), and their interaction with other proteins (metabolizing enzymes, the target protein). Binding to plasma proteins also prevents highly insoluble compounds from precipitating upon iv dosing and helps to distribute such drugs throughout the body. The half-life of peptides may be increased by preventing their renal excretion through enhanced binding to albumin. This can be achieved by acylating the peptide with fatty acids or other plasma protein binding compounds. Plasma protein binding is usually determined by equilibrium dialysis or ultrafiltration. Both techniques exploit the ability of certain membranes to be permeable to small molecules but not to proteins or protein-bound small molecules. The clinical relevance of plasma protein binding has been questioned [4]. • Volume of distribution (V): Amount of drug in the body divided by its plasma concentration. The volume of distribution is the volume of solvent in which the dose would have to be dissolved to reach the observed plasma concentration. Compounds with small volumes of distribution (i.e., high plasma concentration) are often hydrophilic or negatively charged molecules that do not diffuse effectively into muscle and adipose tissue. Compounds strongly bound to plasma proteins will show small volumes of distribution as well. Hydrophobic and/or positively charged molecules, however, readily dissolve in fat and interact strongly with the negatively charged cell surfaces (phospholipids) and, often, have large volumes of distribution (i.e., low plasma concentrations). Experimental and computational methods have been developed to estimate the volume of distribution in humans [5]. 1.1 Pharmacokinetics–Structure Relationship 7

The typical volumes of body ﬂuids are as follows:

Plasma 0.04–0.06 l kg−1 Blood 0.07 l kg−1 Extracellular ﬂuid 0.15 l kg−1 Total body water 0.5 l kg−1

The ‘‘ideal’’ volume of distribution depends on the targeted half-life and pharmacological activity. For antibiotics or antivirals directed toward intracellular pathogens, a high tissue distribution (large volume of distribution) would be desirable. For short-acting anesthetics or antiarrhythmics or for compounds with a low safety margin, smaller volumes of distribution may enable a better control of drug plasma levels. • Clearance (CL): The rate at which plasma is freed of drug, the remainder of the drug diluting into the freed volume. If a constant concentration C of a drug is to be attained, the infusion rate must be CL ×C. CL is related to other PK parameters: CL = dose/AUC = ln 2 × (V/t1/2). The liver blood ﬂow in humans is about 25 ml min−1 kg−1.

With the aid of high-throughput in vitro assays, potency and selectivity at a given target protein can often be rapidly attained. The most promising strategy for ligand optimization is to start with a small, hydrophilic (i.e., leadlike, not druglike) compound identified by screening leadlike compounds at high concentrations (leads are usually smaller, more hydrophilic, and less complex than drugs and show lower affinity to proteins). Then, potency and selectivity is enhanced by systematically introducing lipophilic groups of different shapes at various positions of the hit [6]. Numerous examples of such optimizations have been reported; three examples are shown below (Scheme 1.2 [6c, 7], see also Chapter 72; discovery of losartan). Unfortunately, the structure–activity relationship (SAR) resulting from such examples is of little use for medicinal chemists, as these only hold for specific target proteins and lack general applicability. Far fewer examples have been reported of the optimization of PK and ADME because this requires large amounts of compound and tedious, expensive in vivo assays. Because few compounds reach the clinic, human data are scarce. The ADME properties of xenobiotics are always determined by their interaction with the same set of proteins. Therefore, the study of PK–structure relationships should provide the medicinal chemist with valuable general guidelines for the optimization of leads. Structural features that strongly modulate ADME will always do so, no matter what the target protein of the drug might be. Therefore, a thorough understanding of ADME– and PK–structure relationships should greatly facilitate the design of high-quality development candidates. 8 1 The Drug Discovery Process

O O

DNA gyrase inhibitors O O

O S O S

N N N N N N N N H H H H Maximal noneffective concentration: >250 µg ml−1 8 µg ml−1 0.25 µg ml−1 0.03 µg ml−1

(K D = 10 mM)

Inhibitors of heat shock protein 90 CF CF HN CF 3 3 O 3 N

N OMe N O N O N O

H2N N H2N N H2N N H2N N Cl Cl Cl Cl Cl Ki 8300 nM130 nM 50 nM 7 nM (Hsp90)

DPP-IV inhibitors

O O

HN N N N N NH N NH O N N O N N DPP-IV 3900 nM 200 nM IC50

O O O NH2 NH2 N N N N N N O N N O N N DPP-IV 35 nM 5 nM IC50

Scheme 1.2 Examples of the enhancement of binding afﬁnity of small molecules to speciﬁc proteins. 1.2 The Future of Small-Molecule Drugs 9

1.2 The Future of Small-Molecule Drugs

The number of new drugs reaching the market has steadily declined in recent decades, despite steeply increasing R&D expenditures. Thus, while 53 new molecular entities were approved by the US Food and Drug Administration (FDA) in 1996, only 17 attained approval in 2007. Moreover, many ‘‘new drugs’’ are not really new but just resolved racemates, metabolites, prodrugs, or new formulations of older drugs. Thus, the proton pump inhibitor nexium, which ranged among the top 10 best-selling drugs worldwide in 2006, is just resolved omeprazole, launched 1988, and thus no true innovation. The reasons for this decline in productivity are manifold:

1) Because we have gained a deep understanding of biochemistry and pharmacology, many drug discovery programs start with a target protein and a hypothetical biochemical mechanism. This requires the development of a potent, selective ligand before any proof-of-principle is possible. Because of the high complexity and redundancy of biochemical pathways, however, most hypothetical therapeutic principles will not work in animals. 2) Instead of testing compounds directly in animals, we rely too much on in vitro assays. Earlier, the discovery of new drugs was mainly based on in vivo assays, as only few in vitro assays were available. An in vivo assay will only yield a positive result if compounds are sufficiently soluble and lipophilic to reach the target protein and are neither metabolized too rapidly nor removed by active transport mechanisms and if the whole therapeutic concept works. Toxicity and unwanted side effects will also be rapidly recognized in an in vivo assay. Thus, by testing compounds directly in animals, efficacy data and a large amount of additional information are obtained. In fact, many older drugs were successfully launched before their biochemical mode of action was understood, and many successful drugs, for example, neuroleptics such as top-selling olanzapine or aripiprazole are highly unselective and would probably have been discarded by modern screening plans. To limit oneself to in vitro assays or to neglect disappointing in vivo results (‘‘a more potent compound should do it’’) can quickly cost a lot of time, which may have been spent on a more promising project. If a compound cannot reach its target or if the underlying biochemical hypothesis is flawed, an increase in potency or selectivity will not do the job. 3) Advances in molecular modeling and the availability of X-ray structural analyses of proteins cocrystallized with small ligands have ignited further hopes for ‘‘in silico’’ drug discovery. Results up to now have mostly been disappointing. Molecular modeling may be a useful source of inspiration for medicinal chemists and has on occasions succeeded to improve potency and selectivity of a ligand, but the large number of failures remains unreported [8]. Although proteins are flexible and readily change their conformation and adapt to new ligands, most current molecular modeling packages keep the protein 10 1 The Drug Discovery Process

structure fixed while docking new ligands [9] and do not automatically include water or ions in the docking process [10]. Even if faster computers and more sophisticated software would overcome these limitations, that would not be sufficient. The prediction of solubility, ADME properties, and chemical stability would also be required [11]. Progress in this field is rapid, but there is still a long way to reliable in silico drug development. 4) Development time and costs have increased significantly, because more potential side effects of drugs are continuously being discovered, requiring the identification of much more selective compounds than earlier. While the discovery of paroxetin (1992, Ferrosan) only required the synthesis and testing of ∼130 compounds to optimize few parameters, today much larger numbers of compounds are prepared in most discovery projects because a larger number of parameters must be optimized. Between identification of a drug and FDA approval, long development times are often required: taxol, 1971–1992; omeprazole, 1979–1988; fluoxetine, 1972–1985 [12]. The normal time of patent protection (20 years) is, therefore, inadequate for drugs. Unless the time of patent protection for drugs is extended, prices of new drugs will continue skyrocketing. 5) The advent of parallel synthesis in the mid-1990s has enabled medicinal chemists to prepare many compounds quickly, using unsophisticated chemistry. Little time is left, however, to consider test results carefully and to design and prepare the right compound, no matter how difficult or automatable its synthesis. Despite the large numbers of test compounds prepared, the output of new drugs keeps falling. 6) Computers have invaded our offices and laboratories. Instead of training their key skills, chemists and technicians are wasting their time learning how to use databases, virtual screening software, electronic laboratory journals, and trying to keep up with the ever-growing flood of irrelevant emails. In some companies, chemists and technicians are even burdened with accounting tasks and Six Sigma drills. With all these distractions, no sustained focus is possible any longer, and we are losing our expertise in classical medicinal chemistry and organic synthesis. Today, too few hours are spent in front of the hood, and too few experiments are performed [13]. In their assay ‘‘The role of the medicinal chemist in drug discovery – then and now’’ [14], Lombardino and Lowe suggest that the efficiency of drug discovery may be improved by (i) performing more in vivo assays earlier in the projects; (ii) by including in each discovery team a ‘‘drug champion,’’ that is, an older, experienced scientist to provide historical perspective (‘‘institutional memory’’) and background information (this book can help); and (iii) by continuous training of young medicinal chemists. I would also propose a return to less molecular modeling, less software but more thinking instead, and less parallel synthesis, in particular during the lead optimization phase, where not chemistry but only structure–property relationships should be the driving force of the project. For a number of devastating diseases (cancer, multiple sclerosis, bacterial infections with antibiotic-resistant strains, Alzheimer’s disease, etc.), no cure is References 11 available today. Governmental ‘‘regulation’’ of drug prices is forcing pharmaceutical companies to focus only on high-margin areas but will ultimately preclude any commercial development of new drugs. If politicians believe that medical treatment must be free of charge then the government will also have to provide the new drugs. Only the taxpayer can be forced to finance loss-making ventures forever. However, do politicians really have incentives to improve and extend the life of pensioners even further? The development of new drugs requires a huge and sustained effort and will only occur in a free society with strong economic incentives and a strong protection of individual property rights. As our democracies continue to degenerate toward socialistic kleptocracies, and governmental size, harassment, and plunder expand, the number of new innovative drugs will keep shrinking [15].

References

1. Newman, D.J. (2008) Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J. Med. Chem., 51, 2589–2599. 2. Wermuth, C.G. (2004) Selective optimization of side activities: another way for drug discovery. J. Med. Chem., 47, 1303–1314. 3. Proudfoot, J.R. (2002) Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg. Med. Chem. Lett., 12, 1647–1650. 4. Rolan, P.E. (1994) Plasma protein binding displacement interactions – why are they still regarded as clinically important? Br. J. Clin. Pharmacol., 37, 125–128. 5. (a) Hollosy,´ F., Valko,´ K., Hersey, A., Nunhuck, S., Keri,´ G., and Bevan, C. (2006) Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning. J. Med. Chem., 49, 6958–6971; (b) Lombardo, F., Obach, R.S., DiCapua, F.M., Bakken, G.A., Lu, J., Potter, D.M., Gao, F., Miller, M.D., and Zhang, Y. (2006) A hybrid mixture discriminant analysis–random forest computational model for the prediction of volume of distribution of drugs in human. J. Med. Chem., 49, 2262–2267; (c) Gleeson, M.P., Water, N.J., Paine, S.W., and Davis, A.M. (2006) In silico human and rat Vss quantitative structure – activity relationship models. J. Med. Chem., 49, 1953–1963; (d) Lombardo, F., Obach, R.S., Shalaeva, M.Y., and Gao, F. (2002) Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J. Med. Chem., 45, 2867–2876; (2004) J. Med. Chem., 47, 1242–1250. 6. (a) Congreve, M., Chessari, G., Tisi, D., and Woodhead, A.J. (2008) Recent developments in fragment-based drug discovery. J. Med. Chem., 51, 3661–3680; (b) Hajduk, P.J. (2006) Fragment-based drug design: how big is too big? J. Med. Chem., 49, 6972–6976; (c) Boehm, H. et al. (2000) Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J. Med. Chem., 43, 2664–2674; (d) Maly, D.J., Choong, I.C., and Ellman, J.A. (2000) Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors. Proc. Natl. Acad. Sci. U.S.A., 97, 2419–2424; (e) Hajduk, P.J., Meadows, R.P., and Fesik, S.W. (1997) Discovering high-affinity ligands for proteins. Science, 278, 497–499; (f) Hann, M.M., Leach, A.R., and Harper, G. (2001) Molecular complexity and its impact on the probability of finding leads for drug discovery. J.Chem.Inf.Comput.Sci., 41, 856–864; (g) Oprea, T.I., Davis, A.M., Teague, S.J., and Leeson, P.D. (2001) Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci., 41, 1308–1315. 12 1 The Drug Discovery Process

7. (a) Zehnder, L. et al. (2011) Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of Heat Shock Protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2- difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide. J. Med. Chem., 54(9), 3368–3385; (b) Eckhardt, M. et al. (2007) 8-(3-(R)-Aminopiperidin-1-yl)-7-but-3-ynyl- 3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 50, 6450–6453. 8. Warren, G.L. et al. (2006) A critical assessment of docking programs and scoring functions. J. Med. Chem., 49, 5912–5931. 9. Cozzini, P. et al. (2008) Target flexibility: an emerging consideration in drug discovery and design. J. Med. Chem., 51, 6237–6255. 10. Michel, J., Verdonk, M.L., and Essex, J.W. (2006) Protein–ligand binding affinity predictions by implicit solvent simulations: a tool for lead optimization? J. Med. Chem., 49, 7427–7439. 11. Selick, H.E., Beresford, A.P., and Tarbit, M.H. (2002) The emerging importance of predictive ADME simulation in drug discovery. Drug Discov. Today, 7, 109–116. 12. Wong, D.T., Perry, K.W., and Bymaster, F.P. (2005) The discovery of fluoxetine hydrochloride (prozac). Nat. Rev. Drug Discov., 4, 764–774. 13. Kubinyi, H. (2003) Drug research: myths, hype and reality. Nat. Rev. Drug Discov., 2, 665–668. 14. Lombardino, J.G. and Lowe, J.A. III (2004) The role of the medicinal chemist in drug discovery – then and now. Nat. Rev., 3, 853–862. 15. (a) Ridley, M. (2010) The Rational Optimist. How Prosperity Evolves, Fourth Estate, London; (b) Bastiat, F. (1996, first publishing date: 1845) The physiology of plunder, Economic Sophisms, Irvington-on-Hudson, The Foundation for Economic Education, Inc., New York http://www.econlib.org/library/Bastiat/basSoph5.html#S.2, Ch.1. 13

2 Lead Optimization

The development of a new drug is an iterative process in which a hit or lead is systematically modified until a compound with all the desired biological properties is found. After initial identification of a weakly active substance, the first properties to be improved are usually potency and selectivity at the target protein. Such optimization is often quite straightforward because it only requires in vitro assays, which can be performed quickly and for a large number of compounds. While developing a drug, however, most time is often spent with the improvement of pharmacokinetic (PK) parameters of a lead: its oral bioavailability (F), plasma half- life (t1/2), and ability to cross the blood–brain barrier (bbb; central nervous system (CNS) drugs only). Moreover, any new drug should ideally neither inhibit nor induce liver enzymes (cytochrome P450 (CYP)), be a P-glycoprotein (P-gp) substrate, or interact with human ether-a-go-go` related gene (hERG). The optimization of PK parameters is, unfortunately, much slower than the optimization of in vitro potency and selectivity because it requires in vivo assays and larger amounts of substance. Because the potency and selectivity of leads is often enhanced with additional lipophilic groups, lead structures tend to become too large and too lipophilic. This may be recognized late because potency and selectivity are usually optimized in vitro, where poor solubility is only a minor issue. However, poor solubility is an important reason for the failure of development candidates. To increase the chances of success, some simple rules of thumb have been proposed to estimate whether a compound is likely to have acceptable absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters. One is the famous ‘‘rule of five,’’ which recommends a molecular weight <500 g mol−1,a log P <5, a number of H-bond donors (acidic X–H groups) <5, and less than 10 hydrogen bond acceptors [1]. Other authors recommend even lower molecular weights (e.g., <400 g mol−1) and log P values <4 [2]. A glance at the tables in later sections of this book confirms that most drugs, in particular orally available drugs, indeed lie within a rather narrow range of molecular weights and log P values [3]. Interestingly, drug candidates with one or more sp3-hybridized carbon atoms show a higher success rate than ‘‘flat’’ molecules, which may be due to the low solubility of purely aromatic compounds [4]. There are many successful drugs that do not conform to the general recommendations. For instance, antibacterials are often heavy molecules with

a large polar surface area (PSA) [5]. Antibacterials must overcome the bacterial cell membranes and defense mechanisms, which entails some special physicochemical requirements. When searching for new antibiotics, antifungals, or antiseptics, it may not be a good choice to screen ‘‘general-purpose’’ compound libraries biased toward nonantibiotics.

2.1 What Limits/Reduces Oral Bioavailability?

Oral bioavailability F is defined as the fraction of an orally administered drug reaching systemic circulation. It can be determined by dividing the area under the curve (AUC, plot of concentration vs time) of an oral dose by the AUC of the same dose given intravenously. F depends on the extent to which the drug is absorbed from the gastrointestinal tract and on the extent to which it is destroyed during first-pass metabolism and excreted into the intestinal tract in the bile. Because the function of the stomach is mainly digestive and its surface is small, drugs are usually not absorbed from the stomach but from the intestine. The gastrointestinal (GI) tract may be viewed as a large lipophilic membrane with small, hydrophilic pores with a diameter of 3–8 A.˚ Critical parameters for absorption of compounds from the gut are the PSA, ionization, molecular weight, solubility, energy required for desolvation from water (i.e., hydrogen bonding), and the number of rotatable bonds [6]. Absorption from the intestine starts to drop at a PSA > 60 A˚ 2 and becomes negligible at a PSA >140 A˚ 2. Charged or hydrophilic compounds are only efficiently absorbed if their molecular weight is <150–200 g mol−1 (the lower the better) or if the molecules are long and thin or by means of an active transport mechanism. Lipophilic, uncharged compounds are more readily absorbed but must be soluble in water to a certain extent, in order to come into close contact with the epithelium of the intestine. Large, lipophilic molecules of low solubility or polymers (no matter if soluble or not) are not significantly absorbed from the gut. It has been suggested that a low number of rotatable bonds may also be conducive to better oral bioavailability [7]. Interestingly, molecules with ‘‘intramolecular’’ charge separation, such as mesoionic compounds (e.g., molsidomine), nitro compounds, pyridine N-oxides, azides, and so on, are much more lipophilic than organic cations or anions and are usually well absorbed. In contrast to the stomach (pH 1–3), the content of the intestine is almost neutral (pH 5–8). Strong acids (sulfonic or phosphonic acids and phosphates) or strong bases (amidines and guanidines) can only be absorbed if their molecular weight is sufficiently low. Carboxylic acids can be absorbed from the stomach but are mainly absorbed from the intestine. Before reaching systemic circulation, compounds absorbed from the GI tract are directed by the portal vein to the liver, where CYP enzymes catalyze the hydroxylation and oxidation of lipophilic xenobiotics (phase I biotransformations), 2.2 What Limits/Reduces Plasma Half-Life? 15 to speed up their renal excretion. Hydroxylation may be followed by conjugation to glucuronic acid, amino acids, or sulfate (phase II biotransformations), which facilitates further the excretion in urine. High oral bioavailability can only be attained if the drug is resistant to CYP-mediated chemical transformations. This can be achieved either by fine-tuning the log P and the PSA or by blocking hydroxylation, for example, by fluorination or introduction of heteroatoms at or near the site of hydroxylation. Alternatively, a drug subject to high first-pass metabolism may be formulated in combination with a compound that blocks liver metabolism (e.g., ritonavir). Charged compounds formed in the liver are often excreted into the intestine in the bile, reabsorbed from the intestine, and finally, excreted in the urine. Biliary or enterohepatic recirculation refers to a repetitive excretion of a drug into the bile, followed by reabsorption from the small intestine. Drugs for oral dosing need not be 100% orally bioavailable. High first-pass metabolism may be acceptable for an oral drug if its metabolites are safe and efficiently excreted. Low bioavailability owing to extensive first-pass metabolism may, however, cause a high interindividual variability of F,aswellasahigh dependency of F on additional factors (food, age, CYP inhibitors/inducers, liver or other diseases). Such drugs are difficult to dose correctly.

2.2 What Limits/Reduces Plasma Half-Life?

Blood is constantly being filtered by the kidneys, at a rate of 7.5 l h−1. Thereby, compounds with molecular weights <50 000 g mol−1 are excreted and then partly reabsorbed again into plasma. In addition to passive glomerular filtration, organic cations and organic anions may be renally excreted by an active transport mechanism (‘‘active tubular secretion’’). Plasma proteins and the protein-bound fraction of a drug are not eliminated by renal filtration. The extent to which drugs are reabsorbed varies strongly. Charged organic molecules are generally reabsorbed to a lesser extent than neutral, lipophilic compounds. The only generally applicable strategy to contain renal excretion of a drug is to enhance its binding to plasma proteins or its volume of distribution. Enzymatic activity capable of destroying a drug is mainly located in the liver, gut, kidneys, lung, and skin. In addition to CYP enzymes, drugs will be exposed to alcohol dehydrogenase, various oxidases and reductases, esterases, phosphatases, and proteases. Moreover, blood contains strong nucleophiles (glutathione, cystein; these are further activated enzymatically, e.g., by glutathione transferases), an electrophilic methylating reagent (S-adenosylmethionine), and the electrophilic acetylating reagent acetyl-CoA (in combination with acetyl transferases). All these enzymes and reagents may inactivate a drug or convert a prodrug into the active drug. The liver receives about 75% of its blood supply from the portal vein and 25% from the systemic circulation. Accordingly, parenteral administration of a drug 16 2 Lead Optimization

circumvents to a large extent oxidative enzymatic degradation by the liver. CYP inhibition or induction is also less critical for parenterally dosed compounds.

2.3 How to Improve bbb-Penetration?

The bbb is an additional protection of the CNS from potentially dangerous xenobiotics. Moreover, many drugs are actively excreted from the CNS by P-gp, the product of the multidrug resistance gene, which acts as an active efflux system for a variety of drugs [8]. The bbb is essentially lipophilic and impermeable to large molecules. Only uncharged, lipophilic compounds (log P > 0) with a molecular weight <400–600 g mol−1 and few rotatable bonds can diffuse into the CNS. Hydrogen- bonding ability is highly detrimental for bbb passage, and as a rule of thumb, drugs 2 with a PSA >40 A˚ will not enter the CNS to any significant extent [9]. Even a single carbonyl group (e.g., a ketone, amide, urea, carbamate, etc.) will strongly reduce the ability of a drug to cross the bbb. Strong binding to plasma proteins, which correlates with the log P, may also reduce bbb penetration [10]. Nutrients reach the CNS by means of substrate-specific carriers and active transport mechanisms.

2.4 How to Avoid CYP Inhibition/Induction?

A number of models of the various CYP enzymes have been generated [11] and may be used to predict if a compound is likely to interact strongly with one or more of these enzymes. There is, however, no reliable method to ascertain if the compound will just be a substrate or an inhibitor of the enzyme. This must usually be determined empirically during lead optimization [12]. Molecules capable of strongly coordinating to iron cations (imidazoles and pyridines) may also be CYP inhibitors. In such instances, affinity to CYP can sometimes be lowered by sterically shielding the iron binding site in the inhibitor. Metabolically resistant molecules can be CYP inducers. For instance, the expression and activity of rat liver enzymes is strongly enhanced if the rat is treated with chlorinated biphenyls. Hence, stabilization of a lead to block metabolic transformations may backfire and should not be exaggerated. Drugs with too long half-lives are, moreover, difficult to dose and may lead to dangerous accumulation, above all in older patients. Two famous examples of dietary CYP inhibition and induction are grapefruit and St. John’s wort. Grapefruit and orange juice contain potent inhibitors of CYP3A4/5, which can cause extended half-lives and dangerously high plasma levels of drugs that are metabolized by CYP3A4/5. St. John’s wort and other herbal extracts are CYP inducers and will generally shorten the half-life of many drugs, for example of contraceptives, causing unpleasant surprises here and there. Some 2.6 How to Prevent Toxicity? 17 fruit juices can decrease the oral bioavailability of drugs as well (e.g., of celiprolol and fexofenadine) [13]. If a valuable lead is a potent CYP inhibitor/inducer or too hepatotoxic, a parenteral formulation may still be viable. CYP inducers : barbiturates, carbamazepine, dexamethasone, efavirenz, ethanol, felbamate, growth hormone, isoniazid, moricizine, nevirapine, omeprazole, phenobarbital, phenytoin, prednisone, probenecid, rifampin, rifapentine, ritonavir, smoke, troglitazone, and vegetables; CYP inhibitors : amiodarone, cimetidine, ciprofloxacin, clarithromycin, diltiazem, diphenhydramine, enoxacin, erythromycin, fluconazole, fluoxetine, fluvastatin, fluvoxamine, grapefruit, grepafloxacin, haloperidol, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nefazodone, paroxetine, quinidine, ritonavir, sertraline, sulfamethoxazole, thioridazine, ticlopidine, and verapamil.

2.5 How to Avoid Interaction with the Human Ether-a-go-go-Related` Gene (hERG)?

It is known since long that some drugs can cause cardiac arrhythmias, but these are usually not life threatening. The long QT syndrome, however, may cause torsades de pointes, a ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death by cardiac arrest. The QT interval is the time for both the ventricular depolarization and repolarization. QT-prolonging drugs block potassium channels encoded by hERG. A number of drugs had to be withdrawn for causing prolonged QT syndrome while showing high affinity to hERG, for example, clobutinol, astemizole, grepafloxacin, cisapride, and terfenadine. The relationship between hERG affinity and QT prolongation is, however, not yet firmly established. Clemastine, for instance, has a high affinity to hERG (12 nM) but does not induce QT prolongation [14]. Grepafloxacin, on the other hand, which only binds to hERG with micromolar affinity [15], had to be withdrawn one year after launch following reports of severe QT prolongation. Some SAR (structure–activity relationship) models for the hERG potassium channel have been published and may be used to gain some inspiration if hERG is a problem [16]. hERG counterscreens should be included in every lead optimization program.

2.6 How to Prevent Toxicity?

Strong electrophiles are often toxic or mutagenic because of covalent bond formation with proteins and nucleic acids. Moreover, many nonelectrophilic organic molecules may be converted into electrophilic metabolites in the human 18 2 Lead Optimization

body. This reactivity is difficult to predict and often emerges only during clinical trials or after launch. Drugs may also be phototoxic, that is, sensitize the skin for UV absorption or induce photoallergy (the drug undergoes a photochemical transformation into an allergen). Molecules with suitable chromophores include the quinolone antibiotics, methoxsalen, hypericin, aromatic sulfonamides, tetracyclines, and phenothiazines. Adverse drug reactions include the typical symptoms of overdosing (skin rashes, agranulocytosis, hepatotoxicity, and aplastic anemia), which are usually observed during preclinical development, and the less frequent, sometimes idiosyncratic reactions, which are first recognized once the drug has been widely marketed. In the early 1990s, the main reason for stopping drug development was poor PK. By adding ADMET specialists to the discovery teams, this problem became less acute. Today, the major causes of failure during clinical trials and early withdrawal of drugs from the market are lack of efficacy and excessive toxicity [17]. Although toxicity in humans cannot be predicted, the success rate of drug candidates may be enhanced by avoiding substructures known to cause adverse drug reactions. These include electrophilic groups or groups susceptible to the formation of electrophilic metabolites (Table 2.1). Many drugs contain the functional groups listed in Table 2.1 but do not cause adverse drug reactions because efficient detoxication pathways exist. Moreover, even compounds devoid of any critical functional group can be hepatotoxic (e.g., ximelagatran, Table 55.2). Nevertheless, the risk of excessive toxicity can be lowered by avoiding the groups shown in Table 2.1. One crucial factor for drug safety is the dose: adverse drug reactions are rarely seen for drugs dosed below 20 mg per day. Thus, drug safety may be enhanced by increasing potency or by improving oral bioavailability. One example of metabolic activation is the antiinflammatory sudoxicam (Table 63.1), which is metabolized to a hepatotoxic thiourea [18]. This transformation could be blocked by methylation of the thiazole ring. In the resulting meloxicam, the main metabolic path is hydroxylation and oxidation of this newly introduced methyl group.

Table 2.1 Functional groups prone to the formation of electrophilic metabolites [17a].

Haloalkanes Hydroquinones Imides Alkenes Catechols Thioureas Electron-poor alkenes Aromatic thiols Sulfonylureas Alkynes Cyclopropylamines Formaldehyde acetals Phenyl groups Benzylamines 3-Methylindoles 4-Unsubstituted benzyl ethers Hydrazines 5-Hydroxyindoles Ethoxybenzenes Hydroxylamines Unsubstituted furans Bromoarenes Azides Unsubstituted thiophenes Nitroarenes Hydroxamic acids Unsubstituted thiazoles Anilines Tetrahydropyridines Unsubstituted oxazoles Aminophenols Formamides Thiazolidinediones 2.6 How to Prevent Toxicity? 19

Two further examples of drugs that cause adverse drug reactions because of metabolic activation are clozapine and felbamate. Clozapine contains an electron- rich aniline substructure, which can be oxidized by hydride abstraction to yield an electrophilic, cationic ortho-quinone diimine (Scheme 2.1). This metabolite reacts with nucleophiles and can arylate nucleic acids or the thiol groups of vital proteins. A signiﬁcant number of patients taking this drug develop agranulocytosis [19]. This metabolic activation is also possible in olanzapine but less problematic because of the 30-fold lower dosing of olanzapine. In the clozapine analogs quetiapine and loxapine, the stability toward oxidants was enhanced by replacing the aromatic NH group by S and O.

N N N hydride N abstraction N N N in vivo N NuH N Cl Cl Cl N N N H H Clozapine electrophilic Nu t1/2 12 h, F 55% metabolite Nu = nucleophile daily dose: 300 mg (thiol or amine) agranulocytosis in 2% of patients

N N O N OH N N N N N N Cl N S S O H Olanzapine Quetiapine Loxapine t1/2 27–39 h, F 60–80% t1/2 6–7 h, F 9% t1/2 15 h, F 30% daily dose: 10 mg daily dose: 300–400 mg daily dose: 60–100 mg safe and successful drug safe and successful drug safe drug

Scheme 2.1 Metabolic activation of clozapine.

The ability of a drug candidate to act as hydride donor should be easy to detect by treatment with a mild oxidant, such as benzoquinone. It would have been more difﬁcult, however, to correctly predict the metabolic fate of felbamate. Felbamate is an anticonvulsant bis-carbamate. Within a year of its launch in 1993, 34 cases of aplastic anemia and 23 cases of hepatotoxicity occurred, resulting in 18 deaths. This led to a severe restriction of the use of this drug. The metabolic activation of felbamate proceeds via hydrolysis to a primary alcohol, followed by oxidation to an aldehyde (Scheme 2.2). Elimination to form an α,β-unsaturated aldehyde is particularly easy in this instance because the newly formed alkene is conjugated with the phenyl group. The resulting Michael acceptor, at the high doses required, led to the adverse drug reactions in patients [20]. 20 2 Lead Optimization

O O O enzymatic Felbamate H2N O O NH2 hydrolysis H2N O OH t1/2 21 h, F > 90% daily dose: >3000 mg

oxidation H2N O O β-elimination O highly reactive Michael acceptor, alcohol strong electrophile dehydrogenase

Scheme 2.2 Metabolic activation of felbamate.

With in vitro assays, it is possible to predict toxicity with some precision, but false-positives and false-negatives are common [21]. Similarly, animal models do not reveal human poisons accurately. However, our analytical tools are becoming increasingly sensitive, and our knowledge on metabolic pathways is continuously growing. A better understanding of human metabolism and metabolism-dependent toxicity will lead to advanced toxicity models [22], which will improve our ability to exclude questionable compounds early during drug development.

2.7 Examples of PK-Optimization in Animals

2.7.1 Dihydroorotate Dehydrogenase Inhibitors

CN CN H H N N

O OH O OH R R

R t1/2 (po, rat) R t1/2 (po, rat)

MeS- <1 h Cl- 2 h F3CS- 2 h F3C- 4 h F3CS(=O)- 3 h Br- 4 h O2N- 4 h F3CO- 4 h NC- 5 h NC- 6 h

MeC(=O)- 6 h F3C–CF2- 10 h F3C- 8 h F3CS- 13 h F3CS(=O)2- 14 h Br- 20 h Cl- 22 h F3CO- 22 h 4-Cl(C6H4)O- 39 h 2.7 Examples of PK-Optimization in Animals 21

Kuo, E.A. et al. (1996) Synthesis, structure–activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy- N-[3-methyl-4-(triﬂuoromethyl)phenyl]propenamide and related compounds. J. Med. Chem., 39, 4608–4621.

2.7.2 Matrix Metalloproteinase Inhibitors

O O O O S S N CO H N CO H H 2 H 2

R Br F

R t1/2 (rat, po) R t1/2 (rat, po) t1/2 (rat, po) MeO- 0.36 h Cl- 34.1 h 117 h Me- 0.40 h F3C- 37.9 h H- 3.4 h Br- 43.6 h NC- 12.5 h F- 45.5 h O2N- 19.5 h

O’Brien, P.M. et al. (2000) Structure-activity relationships and pharmacokinetic analysis for a series of potent, systemically available biphenylsulfonamide matrix metalloproteinase inhibitors. J. Med. Chem., 43, 156–166.

2.7.3 Antibacterial Aminobenzenesulfonamides

R O O S N N 6 H 1 H2N

R t1/2 (iv, rat) R t1/2 (iv, rat)

4-CH3 1.2 h 5-CH3 2.4 h 4,6-(CH3)2 1.2 h 3-CH3-5-Br 8.2 h 3-CH -5-Cl 3-CH3 1.3 h 3 8.2 h 3-Cl 3-OCH3 1.3 h 8.7 h 3-CN 1.4 h 5-NO2 16.5 h 3-OEt 1.4 h 3,5-Cl2 21.7 h

H 1.5 h 3,5-Br2 21.7 h 6-CH3 1.9 h 5-Cl 21.7 h

5-N(CH3)2 2.1 h 5-Br 24.8 h 3-CN-5-CH3 2.2 h 22 2 Lead Optimization

Seydel, J.K., Trettin, D., and Cordes, H.P. (1980) Quantitative structure–pharmacokinetic relationships derived on antibacterial sulfonamides in rats and its comparison to quantitative structure–activity relationships. J. Med. Chem., 23, 607–613.

2.7.4 Tyrosine Kinase Inhibitors

Metabolism was the main route of drug elimination of this series of aminopyridines. The major route of metabolism in rat and rhesus monkey (but not in dogs) was N-glucuronidation at the aminopyridine. This biotransformation could be suppressed by introduction of an additional methyl group (last compound).

H N N S CN F 100%; t 7.9 h; V 22 l kg−1; CL 24 ml min−1 kg−1 (dog) HN N N 1/2

H N N S CN −1 −1 −1 N N N F 87%; t1/2 7.2 h; V 0.7 l kg ; CL 1.2 ml min kg (dog) O H N N S CN F nd; t 2.0 h; V 0.9 l kg−1; CL 7.4 ml min−1 kg−1 (dog) N N N N 1/2 O H N N S −1 −1 −1 H CN F 99%; t1/2 17 h; V 0.7 l kg ; CL 0.5 ml min kg (dog) N N N N −1 −1 −1 F 43%; t1/2 1.7 h; V 1.3 l kg ; CL 17.2 ml min kg (rhesus) O H N S N − − − H CN F 92%; t 8.8 h; V 1.3 l kg 1; CL 1.7 ml min 1 kg 1 (rhesus) N N N N 1/2 O

Bilodeau, M.T. et al. (2004) Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low afﬁnity for the hERG ion channel. J. Med. Chem., 47, 6363–6372. 2.7 Examples of PK-Optimization in Animals 23

2.7.5 5-HT1A Agonists

H N O OH 2 H N N H

t1/2 60 min (rat) t1/2 120 min (rat) F 2.4% (rat) F 46% (rat)

Lin, C. et al. (1993) Synthesis and biological activity of cis-(3aR)-(–) -2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability. J. Med. Chem., 36, 2208–2218.

2.7.6 Dipeptidyl Peptidase IV Inhibitors; Structural Variations of Sitagliptin

F F O F F NH2 O NH2 O NMe2 N N N N N N F N F N CF CF Sitagliptin 3 3 −1 −1 −1 −1 t1/2 1.7 h; F 76%; CL 60 ml min kg (rat) t1/2 2.7 h; F 9%; CL 87 ml min kg (rat)

F F F F F F HO NH2 O NH2 O N N N N N N F N F N

CF3 CF3 −1 −1 −1 −1 t1/2 1.5 h; F 76%; CL 29 ml min kg (rat) t1/2 2.6 h; F 8%; CL 63 ml min kg (rat)

CF3 F N F F F NH2 O NH2 O CF3 N N N N N N F N F N

CF3 CF3 −1 −1 −1 −1 t1/2 1.9 h; F 9%; CL 94 ml min kg (rat) t1/2 4.1 h; F 19%; CL 50 ml min kg (rat)

Kim, D. et al. (2008) Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from β-aminoamides bearing substituted triazolopiperazines. J. Med. Chem., 51, 589–602. 24 2 Lead Optimization

2.7.7 P-Selectin Inhibitors

CO2H CO2H CO2H OH Cl OH Cl OH Cl

N N N

Lead CF3 − − F 27%; CL 11 ml min−1 kg−1 (rat) F 75%; CL 7 ml min 1 kg 1 (rat) F 67%; CL 0.7 ml min−1 kg−1 (rat)

CO2H CO2H CO2H OH OH OH CF3

N N N CF CF CF 3 HO 3 3 CF3 − − F 93%; CL 3.7 ml min−1 kg−1 (rat) F 44%; CL 1 ml min−1 kg−1 (rat) F 31%; CL 0.4 ml min 1 kg 1 (rat)

Huang, A. et al. (2010) Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(triﬂuoro- methyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efﬁcacy in models of vascular injury. J. Med. Chem., 53, 6003–6017.

2.7.8 β3-Adrenergic Agonists

O OH OH H CO2H H Cl N N O CO2H

Lead Cl N OMe −1 −1 −1 −1 t1/2 2.3 h (iv); F 35%; CL 12 ml min kg (iv) t1/2 8.2 h (iv); F 29%; CL 16 ml min kg (iv) (monkey) (monkey)

OH CO H H OH 2 Cl N H N O

Cl CO2H −1 −1 −1 −1 t1/2 7.7 h (iv); F 82%; CL 6.7 ml min kg (iv) t1/2 19 h (iv); F 83%; CL 0.9 ml min kg (iv) (monkey) (monkey)

Imanishi, M. et al. (2008) Discovery of a novel series of benzoic acid derivatives as potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. J. Med. Chem., 51, 1925–1944 and 4804–4822. 2.7 Examples of PK-Optimization in Animals 25

2.7.9 Vanilloid-1 Antagonists

O HN CF N 3 −1 −1 S O t1/2 6.3 h (iv); F 32%; CL 3.2 ml min kg (iv); V 1.6 l kg−1; (rat) half-life too long! NN

Lead

O HN N N −1 −1 t1/2 2.7 h (iv); F 3%; CL 23 ml min kg (iv); S O N V 4.5 l kg−1; (rat) CF3 NN

O HN N N −1 −1 t1/2 2.7 h (iv); F 51%; CL 13 ml min kg (iv); S O N V 2.8 l kg−1; (rat) F NN

Wang, H. et al. (2007) Novel vanilloid receptor-1 antagonists: 3. The identiﬁcation of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties. J. Med. Chem., 50, 3528–3539.

2.7.10 HIV Protease Inhibitors

OH OH S S

OH OH O O O O S

H2N Lead

t1/2 1.2 h; F 33% (dog) t1/2 5.4 h; F 88% (dog)

Hagen, S.E. et al. (2001) 4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters. J. Med. Chem., 44, 2319–2332. 26 2 Lead Optimization

2.7.11 Matrix Metalloproteinase Inhibitors (Tested in Rats)

O O O O O O HO S HO S OCF N N N 3 H t1/2 0.3 h H t1/2 1.8 h O F 42% O F 7% O N H

O O O O O O HO S CF HO S N 3 N H H t 0.9 h t1/2 1.7 h O 1/2 O F 6% O N F 3% O N

O O O O O O HO S OCF HO S OCF3 N 3 N H H t1/2 1.9 h t1/2 1.1 h O O O F 36% N F 4% O O O O O O O HO S Cl HO S OCF N N 3 H H t1/2 1.5 h t1/2 2.9 h O O O F 46% N F 23%

O O O O O O HO S CF HO S OCF N 3 N 3 H H t1/2 2.7 h t1/2 2.9 h O F 33% O F 68% O N MeO

Becker, D.P. et al. (2010) Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efﬁcacy in cancer, arthritis, and cardiovascular disease. J. Med. Chem., 53, 6653–6680.

2.7.12 HIV Integrase Inhibitors

Both thiophene derivatives were potent in an enzymatic assay but too toxic and weak in a cellular assay. These problems could be solved by replacing the thienyl group by various aminomethyl groups. 2.7 Examples of PK-Optimization in Animals 27

OH OH OH OH F N N H H N N S N S N O Lead O −1 −1 −1 −1 t1/2 3 h, F 15%, CL 5 ml min kg t1/2 1.3 h, F 29%, CL 11 ml min kg (rat) (rat)

OH OH OH F OH F N N H H N N N N N O N O

−1 −1 −1 −1 t1/2 1.7 h, F 59%, CL 14 ml min kg t1/2 2 h, F 28%, CL 16 ml min kg (rat) (rat)

OH O OH F OH F N N H H N N N O N N O N O

−1 −1 −1 −1 t1/2 0.5 h, F 27%, CL 44 ml min kg t1/2 1.1 h, F 56%, CL 9 ml min kg (rat) (rat)

Summa, V. et al. (2006) 4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic proﬁles in preclinical species. J. Med. Chem., 49, 6646–6649.

2.7.13 Dopamine D3 Antagonists

H N H F3C O N −1 −1 S N t1/2 2.5 h; F 7%; CL 27 ml min kg O O O (rat)

H N N −1 −1 H t1/2 6.3 h; F 43%; CL 6 ml min kg NC O (rat) N

N H N −1 −1 t1/2 2 h; F 43%; CL 19 ml min kg O (rat) N

NC 28 2 Lead Optimization

Stemp, G. et al. (2000) Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroiso- quinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): a potent and selective dopamine D3 receptor antagonist with high oral bioavailability and CNS penetration in the rat. J. Med. Chem., 43, 1878–1885.

2.7.14 Inhibitors of Soluble Epoxide Hydrolase (Tested in Mice, po)

O O Cl O N O N

N N t1/2 78 min N N t1/2 381 min H H AUC 19 µM min H H AUC 13600 µM min Lead

O CF3 O Cl O N O N

N N t1/2 56 min N N t1/2 814 min H H AUC 580 µM min H H AUC 5160 µM min

O O F CO O N 3 O N t 72 min N N 1/2 N N t1/2 980 min H H AUC 920 µM min H H AUC 14000 µM min

O O MeO F CO O N 3 O N t 82 min N N 1/2 N N t1/2 1180 min H H AUC 2830 µM min H H AUC 9850 µM min

Rose, T.E., Morisseau, C., Liu, J.-Y., Inceoglu, B., Jones, P.D., Sanborn, J.R., and Hammock, B.D. (2010) 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inﬂammatory pain. J. Med. Chem., 53, 7067–7075. References 29

2.7.15 Melanin-Concentrating Hormone Receptor-1 Antagonists

Rat AUC (0–6 h) Rat AUC (0–6 h) −1 (ng h ml ) (ng h ml−1) F F O O

F3C N N F3C N N H CN H CN 2190 N 1161 OH N F F O O

F3C N N F3C N N H CN H CN 1457 N N 1675 NCH3 N F F O O CN

F3C N N F3C N N H CN H 140 N N 642 NCH3 N

F F O O F

F3C N N F3C N N H CN H CN 450 O 3081 NCH3 N N

McBriar, M.D. et al. (2006) Discovery of orally efﬁcacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas. J. Med. Chem., 49, 2294–2310.

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Part II The Pharmacokinetic Properties of Compound Classes

3 Alkanes

Alkyl groups are often introduced into leads to improve potency and selectivity, or to increase lipophilicity. If the lead is small and hydrophilic, alkyl groups may not only improve the afﬁnity to the target protein but also enhance the oral availability of the compound by improving its absorption from the small intestine. Moreover, higher lipophilicity will improve tissue distribution and thereby increase the volume of distribution, which, at constant clearance, will also extend the half-life of a drug. PK (pharmacokinetic) improvement by enhancement of lipophilicity is exempliﬁed by the adrenergic agonists oxedrine, bamethan, and clenbuterol (Scheme 3.1).

OH OH OH H H H N N Cl N

HO HO H2N Oxedrine Bamethan Cl Clenbuterol − t 1/2 2 h, F 22% t 1/2 2.5 h, F 75% t 1/2 34 h, F 89 98% log P 0.4 log P 1.9 log P 3.0

Scheme 3.1 Effect of alkyl groups on PK properties.

Usually, more or larger alkyl groups will render a compound less water soluble, but occasionally, an additional alkyl group may increase the solubility by lowering the crystal lattice energy. Unbranched alkyl groups lead to a larger increase in lipophilicity than isomeric branched groups (because of the larger lipophilic surface area of straight alkyl groups), as illustrated by the solubilities of isomeric pentanols and hexanols shown in Scheme 3.2 [1].

OH OH OH OH OH OH

23.6 g l−1 28.5 g l−1 37.4 g l−1 56.1 g l−1 106.6 g l−1 121.5 g l−1

Solubility in water ( at 20 °C ) OH OH OH OH OH

7.1 g l−1 9.2 g l−1 24.1 g l−1 44.4 g l−1 84.0 g l−1

Scheme 3.2 Solubility of pentanols, hexanols, and phenol.

Alkyl groups exert a signiﬁcant electron-donating effect, and can lower the acidity of phenols or carboxylic acids, and enhance the electron density at arenes or heteroarenes and the basicity of amines. Such effects may have dramatic consequences for the selectivity, potency, and metabolic stability of a drug. One exception is the cyclopropyl group, which has a slight electron-withdrawing effect because of the sp2-like hybridization of its carbon atoms. Thus, cyclopropylamines or (cyclopropylmethyl)amines are less basic than isopropyl- or isobutylamines (see Chapter 23).

3.1 Metabolism

Alkyl groups can be hydroxylated by liver enzymes. Particularly reactive are benzylic or allylic positions. Methyl groups directly attached to an arene or heteroarene are often hydroxylated or even oxidized to a carboxyl group. As illustrated by the examples in Scheme 3.3, the metabolic fate of alkyl groups is not determined by the structure of the alkyl group alone, but by the structure of the whole molecule. Thus, cyclohexyl groups are often rapidly hydroxylated in positions 4 or 3, but a number of small cyclohexane derivatives, some with long plasma half-lives, do not undergo C-hydroxylation at all. 3.1 Metabolism 37

OH O O O O O O O O O S S N N N N S N N H H H H + H H

O Acetohexamide OH t1/2 7 h O − t 1/2 1 2 h OH

+ N N N OH Phencyclidine − − t 1/2 7 51 h, F 50 90%

SO3Na HN CO H H2N 2 None or little metabolic C-hydroxylation in humans

Gabapentin Cyclamate t 1/2 7 h , F 60% t 1/2 8 h (rat) F < 37%

Scheme 3.3 Metabolism of substituted cyclohexanes.

Similarly, amantadine (Scheme 3.4) is hardly metabolized [2], while the closely related rimantadine undergoes extensive hydroxylation at the adamantyl group. More than 20% of orally administered rimantadine is excreted in the urine as hydroxylated metabolites.

NH2 NH2

Amantadine Rimantadine t 1/2 16 h , F 70% t 1/2 30 h, F 99% (dog) renal excretion unchanged 70% renal excretion unchanged 9%

NH2

Memantine − t 1/2 60 100 h, F 100% renal excretion unchanged 48%

Scheme 3.4 Metabolic stability of adamantylamines. 38 3 Alkanes

Long alkyl chains are usually hydroxylated at the penultimate carbon (ω − 1), and may even be oxidized to carboxylic acids. The latter may be α-hydroxylated, decarboxylated, and oxidized further to yield shorter carboxylic acids. As illustration of typical metabolic reactions of alkyl groups, the human metabolites of nateglinide and irbesartan are shown in Scheme 3.5 [3].

HO HO H H H N CO H N CO H N CO H 2 2 ++2 O O O Nateglinide − t 1/2 1.4 2.9 h F 72% HO CO2H HO OH H H H O O N CO2H N CO2H N ++O OH O O O OH

Nateglinide glucuronide

N N N N N N N N N N N N N NH OH N NH + O N NH

Irbesartan − t 1/2 11 20 h F 60−80% OH

N N N HO N N N N N N N N N OH + O N NH + N NH + N N OH

O OH

CO2H Irbesartan glucuronide

Scheme 3.5 Metabolism of nateglinide and irbesartan.

The metabolic hydroxylation of alkyl groups may be avoided by keeping them small, by substituting hydrogen by ﬂuorine or other heteroatoms, by substituting the alkyl group by chlorine or an alkoxy group, or by rendering the molecule more hydrophilic. Occasionally, structural modiﬁcation of the alkyl group, for example, References 39 the introduction of a methyl, cyclopropyl, or ethinyl group, may also block metabolic hydroxylation, as in the β-adrenergic antagonist betaxolol (Scheme 3.6).

OH OH H H O N O N

Cl O

Bupranolol (log P 3.4) Metoprolol (log P 2.0)

t 1/2 2 h, F < 10% t 1/2 3 h, F 38% (fast oxidation of ArCH3 to ArCO2H) OH H O N

Betaxolol (log P 2.8) − t1/2 14 22 h, F 89%

Scheme 3.6 Metabolic stabilization of methyl ethers by conversion to cyclopropylmethyl ethers.

References

1. (a) Ishikawa, M. and Hashimoto, Y. (2011) Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem., 54, 1539–1554; (b) Ginnings, P.M. and Baum, R. (1937) Aqueous solubilities of the isomeric pentanols. J. Am. Chem. Soc., 59, 1111–1113; (c) Stephenson, R. and Stuart, J. (1986) Mutual binary solubilities: water-alcohols and water-esters. J. Chem. Ing., 31, 56–70. 2. Koppel,¨ C. and Tenczer, J. (1984) A revision of the metabolic disposition of amantadine. Biol. Mass Spectrom., 12, 499–501. 3. Weaver, M.L. et al. (2001) Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab. Dispos., 29, 415–421. 40

4 Alkenes and Alkynes

Because alkenes are chemically reactive and may be metabolized to potentially toxic epoxides, medicinal chemists tend to avoid them. Many olefins such as styrene, allyl alcohol, allylamine, 1,3-butadiene, and vinyl chloride are irritant, hepatotoxic agents, and potential carcinogens. However, several drugs with vinyl or ethynyl groups have been a success, and unsaturation should be considered for pharmacokinetic (PK) fine-tuning and patent avoidance. Toxicity will be less of an issue if a compound is highly potent, and few milligrams will suffice for a one-day treatment. Owing to the higher polarizability of olefins and alkynes, compared to the corresponding saturated compounds, the former tend to be more soluble in water. Vinyl or ethynyl groups are electron withdrawing and can be used to decrease the electron density at arenes or heteroarenes. Allylamines and propargylamines are significantly less basic than the corresponding propylamines, and allyl alcohols are more acidic than propanols (Scheme 4.1 [1]).

NH NH2 2 NH2

pKa 10.7 9.49 7.87 (in water)

OH OH OH Scheme 4.1 The effect of 16.0 15.5 13.6 unsaturation on pKa values.

4.1 Metabolism

The rate and type of metabolization depends on the olefin’s electron density and precise structure. Electron-deficient olefins, such as cinnamic acids, are often hydrogenated in vivo to alkanes. Electron-rich olefins and arenes, however, are mainly epoxidized by liver enzymes. Depending on their structure, these epoxides may be more or less reactive toward nucleophiles. Some epoxides are rather unreactive and can be readily detected in plasma or urine, or even be used as drugs, such as the bronchodilator tiotropium (t1/2 5–6 d), the scopolamines, or the

Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds, First Edition. Florencio Zaragoza Dorwald.¨  2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. 4.1 Metabolism 41 epoxide of carbamazepine. Other epoxides, in particular arene oxides, are highly reactive and will either alkylate P450 enzymes and lead to irreversible cytochrome P450 (CYP) inhibition, or alkylate other proteins or nucleic acids in the liver, leading to hepatotoxicity or hepatocarcinogenicity. The carcinogenicity of benzpyrene, vinyl chloride, and the aflatoxins is caused by metabolic epoxidation. Epoxides do not necessarily lead to enzyme inactivation or to the alkylation of DNA, but may also be hydrated enzymatically to 1,2-diols. Furthermore, the ubiquitous sulfur nucleophile glutathione can also be alkylated by sufficiently reactive epoxides and thereby mediate their detoxification. Unsaturated hydrocarbons may be quickly metabolized to 1,2-diols (via epoxides). This transformation has been used to design drugs with a short half-life. The barbiturate methohexital, for instance, is metabolized faster than other, related barbiturates and has been used as a short-acting, injectable anesthetic (Scheme 4.2). The long half-life and high oral bioavailability of secobarbital, however, shows that metabolic degradation of vinyl groups is not always fast. Particularly long-lived olefins are the piperazine derivatives flunarizine and almitrine.

O O O

N N N

O N O O N O O N O H H H Hexobarbital Mephobarbital Methohexital − t1/2 4 h, F > 90% t1/2 30 50 h, F 75% t1/2 4 h

O F O N Ph HN HN N

O N O O N O H H Secobarbital Pentobarbital Flunarizine − − − F t1/2 19 34 h, F 90% t1/2 35 50 h, F 70 90% t1/2 18 d, F 85%

N N O H2N F N N N N N N H N N N N N O

Almitrine Linagliptin − − F t1/2 55 d, F 70% t1/2 113 130 h, F 15 51% (rat)

Scheme 4.2 Alkene- and alkyne-containing drugs. Epoxidation is not necessarily the fastest metabolic reaction of an alkene. In some oleﬁns, allylic hydroxylation or other metabolic pathways may effectively compete with epoxidation, as, for instance, in the antiarrhythmic quinidine (Scheme 4.3). 42 4 Alkenes and Alkynes

HO HO N N H in vivo H MeO MeO

N N Quinidine 3-Hydroxyquinidine t1/2 6 h, F 80% t1/2 12 h

Scheme 4.3 Metabolism of quinidine.

Allylbenzenes such as estragole or safrole are similarly activated by hydroxylation at the allylic/benzylic position (Scheme 4.4). Sulfation of the resulting allylic alcohol leads to strongly alkylating carcinogens.

O O S OH O OH O in vivo O O

O O O Safrole Nu

O Nu O

Scheme 4.4 Metabolism of safrole.

Not all allylbenzenes are metabolized to allylic sulfates. The short-acting anesthetic acetamidoeugenol, withdrawn for causing local irritation, is converted in vivo to a cinnamic acid, presumably via isomerization and oxidation of an intermediate allylic alcohol (Scheme 4.5 [2]).

MeO MeO CO2H N N O O O O Acetamidoeugenol Main metabolite of acetamidoeugenol t1/2 < 10 min; F: low t1/2 several hours

Scheme 4.5 Metabolism of acetamidoeugenol.

The different metabolic fates of safrole and acetamidoeugenol suggest that metabolism predictions are far from trivial. Several drugs containing oleﬁns or alkynes have been successfully launched and do not show any excessive toxicity. 4.1 Metabolism 43

Therefore, if a lead with a larger alkyl group is too lipophilic or insoluble, an unsaturated analog may be an option to test. Small, hydrophilic drugs containing an alkene, such as seletracetam, vigabatrin, or tilidine (Scheme 4.6), seem not to be metabolized to toxic epoxides. The main metabolic pathway of the irreversible monoamine oxidase (MAO) inhibitor mofegiline in humans and dogs is carbamate formation by carboxylation and intramolecular vinylic displacement of ﬂuoride [3].

F O F O EtO C H N CO H 2 N N 2 2 H2N

Tilidine Seletracetam Vigabatrin t1/2 short, fast demethylation to t 8 h, F > 90% t 4−8 h, F 50−65% − 1/2 1/2 desmethyltilidine (t1/2 3 5 h) metabolism: metabolism: F 99% (of desmethyltilidine on hydrolysis of CONH2 lactam formation oral administration of tilidine)

F F H NH N O 2 in vivo O F F Mofegiline − t1/2 0.7 3.0 h

O O

Scheme 4.6 Alkene-containing drugs and their metabolic transformations.

Relatively few alkyne-containing drugs have been marketed. Notable examples include the obsolete oral hypnotics ethinamate and ethchlorvynol, the contraceptive ethinyl estradiol, and the antineoplastic kinase inhibitor erlotinib (Scheme 4.7). In ethinylestradiol, the ethinyl group effectively blocks enzymatic oxidation to estrone and thus ﬁrst-pass metabolism. Ethinylestradiol has much higher oral availability and longer half-life than the parent estradiol. Metabolic transformations of the ethinyl group of erlotinib are shown in Scheme 4.7. 44 4 Alkenes and Alkynes

OH OH O OH O H H O NH Cl 2 H H H H N HO HO

Ethchlorvynol Ethinamate Talsaclidine Ethinyl estradiol Estradiol − − − t1/2 10 20 h t1/2 2 3 h t1/2 3 h, F 90% t1/2 10 h, F 51% t1/2 < 0.5 h, F 3 5%

HN O OH OH O MeO N in vivo ++HN OH MeO O N HN HN OH R Erlotinib R R − t1/2 36 h, F 60 100%

Scheme 4.7 Alkyne-containing drugs.

References

1. (a) Ballinger, P. and Long, F.A. (1960) Acid ionization constants of alcohols. II. Acidities of some substituted methanols and related compounds. J. Am. Chem. Soc., 82, 795–798; (b) Hine, J., Yeh, C.Y., and Schmalstieg, F.C. (1970) Polar effects on the formation of imines from isobutyraldehyde and primary aliphatic amines. J. Org. Chem., 35, 340–344. 2. Pulver, R. and Litvan, F. (1960) Uber¨ den Stoffwechsel des 2-Methoxy- 4-allylphenoxyessigsaure-¨ N,N-diathylamid.¨ Arzneimittel-Forsch., 10, 111–113. 3. Dow, J., Piriou, F., Wolf, E., Dulery, B.D., and Haegele, K.D. (1994) Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans. Drug Metab. Dispos., 22, 738–749. 45

5 Arenes

Arenes and heteroarenes are ubiquitous structural elements of drugs. Their popularity is mainly due to their good synthetic accessibility. Substituted arenes and heteroarenes are often easier to prepare than saturated cyclic compounds because no stereoisomers are formed and because the regioselectivity of aromatic substitutions is predictable. Moreover, arenes dissolve better in water than cyclohexanes, mainly because of their higher polarizability.

5.1 Metabolism

The metabolic fate of arenes depends not only on the precise substitution pattern but also on the overall structure of the arene-containing compound. The most common metabolic transformation of arenes is hydroxylation via the intermediate formation of an arene oxide (Scheme 5.1).

OH Nu

OH OH O Nu CYP R or

Nu R R R R Arene oxide

Nu: nucleophile (water, thiols, amines, nucleotides) R

Scheme 5.1 Metabolism of arenes.

The reactivity and thus the toxicity and mutagenicity of arenes and arene-derived metabolic intermediates depends on their substituents. While the arene oxides of benzene or benzpyrene are cancerogenic, the arene oxide of bromobenzene mainly reacts with proteins in the liver leading to necrosis. Alkylbenzenes,

such as toluene, are usually not mutagenic but are mainly metabolized at the benzylic positions; phenylalanine is converted to tyrosin. Arenes with electron- withdrawing substituents, such as benzoic acid, or highly substituted arenes are often resistant to metabolic epoxidation. Electron-rich arenes, such as arylethers, alkylarenes, or anilines, are usually metabolized faster than electron-poor arenes (haloarenes, arylketones, and benzoic acid derivatives). The rate of hydroxylation of monosubstituted, electron-rich benzenes can, however, be sufﬁciently slow for their use in drugs (Scheme 5.2).

OH OH O O CO H N 2 O N NH N O HN

F O N O H Atorvastatin Phenylbutazone Phenobarbital − t 1/2 11 58 h t 1/2 56 h t 1/2 99 h F 12% F 90% F 100% Arrow: site of metabolic hydroxylation

Scheme 5.2 Hydroxylation of drugs with electron-rich phenyl groups.

If one’s lead is too short-lived, and aromatic hydroxylation is the fastest metabolic reaction, ﬂuorination of the arene may be an option. Alternatively, if the target permits it, chlorine, alkoxy, acetamido, cyclopropyl, or ethinyl groups may be attached to the site of metabolic hydroxylation. An electron-withdrawing substituent at any position of the arene may also block or retard hydroxylation, as illustrated by the β-adrenergic antagonists in Scheme 5.3. Chlorination of the para position of the dichlorophenoxy group in diclofenac leads to a 30-fold increase of plasma half-life. 5.1 Metabolism 47

OH H L-Penbutolol Arrow: site of metabolic hydroxylation − O N t 1/2 2 5 h F 90-95%

OH OH H H O N Practolol O N O − t 1/2 5 13 h N F 100% H Propranolol OH t 1/2 4 h H O N Levobunolol F 26% O t 1/2 20 h F 80%

CO H CO2H 2 Diclofenac O O Fenclofenac t 1/2 29 h t 1/2 1.1 h Cl Cl Cl F 54%

Scheme 5.3 Metabolism and half-life of arylether-containing drugs.

Large, polycyclic arenes can be highly carcinogenic, and lead to tumors when re- peatedly applied to the skin. This is, however, not the case for smaller hydrocarbons (Scheme 5.4). Chronic exposure to benzene, however, can cause leukemia.

Generate tumors on application to skin No tumors on application to skin

Scheme 5.4 Carcinogenic and non-carcinogenic arenes. 48 5 Arenes

Naphthalene is signiﬁcantly more reactive than benzene or toluene, and few drugs contain unsubstituted 1- or 2-naphthyl groups (Scheme 5.5). Naphthyloxy groups, however, are frequently used and appear to yield only unproblematic metabolites (e.g., 4-hydroxylated 1-naphthyloxy). One metabolite of cinacalcet is a 1,2-dihydroxylated dihydronaphthalene. 1-Naphthylamine has been used to develop anticholinesterase agents (e.g., 1-naphthyl N-methylcarbamate, an insecticide) and rodenticides (1-naphthylthiourea). 2-Naphthylamine and its derivatives are potent carcinogens and are unlikely to be of any use in drug development.

O H N N N O H N O

CF3 Naphazoline Cinacalcet Nafronyl − adrenergic agonist t 1/2 30 40 h t 1/2 1.5 h vasoconstrictor F 20−25% F 30% nasal decongestant OMe EtO NH 2 H H N N S H N O N O O CO2H Terbinafine Agomelatine Nafcillin − − t 1/2 17 36 h t 1/2 1 2 h t 1/2 1 h F 40% F < 5% F 36% H O N N OH H O O N N Adimolol Dapoxetine t 14 h 1/2 t 1/2 18 h F 33−52% F 15−76%

Scheme 5.5 Drugs containing naphthyl groups.

The few monoalkylnaphthalene-containing drugs cannot, in view of the examples in Scheme 5.5, be related to synthetic inaccessibility or biological inactivity alone. A more likely reason may be toxicity or CYP (cytochrome P450) inhibition issues. Suitable alternatives to naphthyl are benzannulated heterocycles, such as benzimidazole, benzpyrazole, benzoxazole, benzothiazole, indole, quinoline, quinazoline, and so on. 49

6 Halides

The properties of the four halogens diverge so much as to merit individual chapters. The only shared property is their ability to act as a leaving group for nucleophilic displacement: organic halides are electrophilic compounds capable of reacting irreversibly with nucleophiles such as thiols, amines, or nucleic acids. However, their ability to do so depends to a large extent on the precise structure of the organic halide. Highly reactive halides, such as benzylic, allylic, α-alkoxy, α-orβ-alkylthio, or α-carbonyl halides, or non-neopentylic alkyl bromides or iodides, are too reactive to be suitable as drugs, unless irreversible alkylation of a protein or nucleic acid is the aim. Vinylic halides may be metabolically activated by epoxidation. Such halides can alkylate DNA and be mutagenic and carcinogenic. A selection of carcinogenic organic halides is shown in Scheme 6.1.

Br Cl OMe Cl Br Cl O Cl

Br O Cl Cl Br Cl Cl Cl Cl

Scheme 6.1 Carcinogenic organic halides.

6.1 Fluorine

Fluorine is a bioisostere of hydrogen. Thus, the physicochemical properties of ﬂuorinated compounds are similar to those of nonﬂuorinated analogs (Scheme 6.2) [1].

NH2 NH2 OH OH F F

F CN H CN bp 79 °C 82 °C 182 °C 183 °C 172 °C 180 °C pKa (H2O) 3.20 4.58 8.81 10.0 log P −0.11 −0.33 1.47 1.14 1.82 1.54

Scheme 6.2 Effects of ﬂuorination.

However, chemically, hydrogen and fluorine atoms behave quite differently. Because C−F bonds are strong, homolytic cleavage is usually not possible; therefore fluorine atoms may be used to block oxidative degradation by liver enzymes. Aromatic nucleophilic substitution or β-elimination of fluoride can, however, readily occur, also in vivo. Single fluorine atoms at sp3-carbon have been used to modulate the selectivity and metabolism of antiinflammatory cortisone analogs and of antineoplastic nucleotide analogs (Scheme 6.3).

F OH O O S OH HO OH HO H H

F H F H O O F Dexamethasone Fluticasone t1/2 3 h, F 78% t1/2 8 h (iv), F < 1%

HO N O O N NH2 H N 2 N N N HO F F N Cl Clofarabine Afloqualone t1/2 5 h (iv), F low t1/2 3.3 h

Scheme 6.3 Fluorinated drugs.

Because alkyl fluorides are not easy to prepare, most examples of single fluorine substitution are at vinylic or aromatic positions. One of the most useful properties of single fluorine atoms is their ability to block metabolic hydroxylation. If this is the rate-determining metabolic pathway, selective fluorination may significantly enhance the plasma half-life and oral availability of a lead. A comparison of cinnarizine with flunarizine clearly illustrates this point. Cinnarizine is mainly metabolized by aromatic hydroxylation of the benzhydryl group, which is no longer possible in flunarizine (Scheme 6.4).

F N N N N

Cinnarizine Flunarizine − t1/2 5 h t1/2 17 19 d F 75−100% F 85% F

Scheme 6.4 Effect of ﬂuorination. 6.2 Chlorine 51

Trifluoromethyl groups are metabolically stable and have been used as highly hydrophobic substituents, similar to methyl groups or chlorine atoms. Also, difluoromethyl, difluoromethoxy, and trifluoromethoxy groups can be used for this purpose. Such substituents not only increase the stability of a compound but also modify its solubility and affinity to proteins. C−F bonds are less polarizable than C−H bonds, and perfluoroalkanes are therefore not attracted by alkanes through induced-dipole–induced-dipole interactions (dispersion or London interactions). Thus, perfluoroalkyl groups are hydrophobic without being lipophilic.

6.2 Chlorine

The chlorine atom is metabolically inert and lipophilic, and well suited to enhance the affinity of a lead to its target protein. Alkyl chlorides are more reactive toward nucleophiles than alkyl fluorides, but often sufficiently unreactive to resist metabolic degradation. Thus, the sedative clomethiazole, the artificial sweetener sucralose, the antiprotozoal ornidazole, and the plant-growth regulator chlormequat are stable and do not react as electrophiles in vivo (Scheme 6.5). However, one of the metabolites of ornidazole is a diol, resulting from the displacement of chloride by hydroxide.

Cl HO OH O2N S Cl O OH Cl N N Cl HO O N O N Cl OH Cl Clomethiazole Sucralose Ornidazole Chlormequat − − − − t1/2 5 h, F 30% t1/2 3 23 h, F 11 40% t1/2 11 14 h, F > 97% t1/2 10 14 h

Scheme 6.5 Alkyl chlorides of low toxicity.

Only benzylic, allylic, or similarly activated chlorides will alkylate nucleophiles under physiological conditions. Bis(2-chloroethyl)amine derivatives, for instance, in which the nitrogen atom assists nucleophilic displacement, are useful as antineoplastics by virtue of their ability to alkylate nucleic acids (Scheme 6.6). The most reactive of them must be given intravenously, but the more unreactive ones, such as chlorambucil, are sufﬁciently stable to permit oral dosing. The irreversible α-adrenergic antagonist phenoxybenzamine is used for treating tumors of the adrenal medulla and sympathetic neurons (pheochromocytomas). 52 6 Halides

Cl Cl Cl N N Cl Cl N O P ONH O Cl Cl N CO2H

Mechlorethamine Chlorambucil Cyclophosphamide Phenoxybenzamine t < 24 h t1/2 < 1 min t1/2 1.3 h, F 87% t1/2 7.5 h, F 74% 1/2

Scheme 6.6 Alkylating drugs.

Vinyl chlorides are less stable than the corresponding vinyl ﬂuorides and can lead to toxic metabolites. Aryl chlorides, however, are metabolically stable unless strongly electron-withdrawing groups facilitate their substitution by an addition–elimination mechanism. Some chlorinated compounds, such as DDT, chlorinated biphenyls, or tetrachlorodioxin, are extremely inert toward metabolic or chemical degradation, which has forced the authorities of most countries to prohibit their preparation and use. Arene-bound methyl groups can often be replaced by chlorine to yield metabolically more stable compounds with similar biological activity. This strategy was used to design long-acting analogs of zolpidem and tolbutamide (Scheme 6.7).

N N Cl O O N N N Cl N

Zolpidem Alpidem − t1/2 2.2 h, F 67% t1/2 18 20 h, F 13% (rat) V 0.54 l kg−1, log P 3.07 V 5 l kg−1 (rat), log P 5.49

O O O O O O S S N N N N H H H H Cl

Tolbutamide Chlorpropamide t1/2 5.9 h, F 93% t1/2 33 h, F > 90% V 0.10 l kg−1, log P 2.36 V/F 0.1 l kg−1, log P 2.30

Scheme 6.7 Methylated versus chlorinated drugs. 6.4 Iodine 53

6.3 Bromine

Alkyl bromides are usually too reactive and cannot be used as drugs, unless an alkylating agent is required. One exception is the chemically unreactive inhalation anesthetic halothane (F3CCHClBr), which can, however, cause liver damage on repeated use. Some aryl bromides are readily debrominated in vivo,suchasthe uricosuric benzbromarone (Scheme 6.8). Many aryl bromides are hepatotoxic. Some, however, seem to be safe, such as the expectorant bromhexine and the antiviral brivudine.

O Br Br N O OH Br Br NH2 Benzbromarone Bromhexine t 3 h − 1/2 t1/2 6 12 h, F 25% metabolism: debromination

H O N O H in vivo O N O HO O N HN Br CO2H HO Brivudine Uracilacetic acid t1/2 16 h, F 30%

Scheme 6.8

Other drugs containing aryl bromides are brodimoprim, brofaromine, brimonidine, bromocriptine (a 2-bromoindole), etravirine, zimeldine, brompheniramine, and a number of benzodiazepines.

6.4 Iodine

The iodine–carbon bond is rather weak, and most iodine-containing drugs will leak small amounts of iodide. Iodine-containing compounds are only used for special applications, namely, as contrast agents, radioactive tracing agents (131I), topical antiseptics, or for the treatment of thyroid-related diseases. More iodinated drugs include iodoquinol (treatment of parasitic infections) and the antiarrhythmic amiodarone (Scheme 6.9). All these agents can cause acute hypersensitivity reactions because some people become allergic to iodine (iodism). 54 6 Halides

O I I

N O O I N I OH Amiodarone Iodoquinol − t1/2 25 h, F 46% t1/2 11 14 h, F 8%

OH H HO N O

I I OH OH H HO N N O I OH O Iohexol t1/2 3 h

Scheme 6.9 Iodinated drugs.

Contrast agents, such as iohexol, are administered intravenously at high doses in the precise moment of the measurement (e.g., computer tomography) and are excreted mainly unchanged in the urine afterward. Heavier halogen atoms in a lead may be replaced by azide, cyano, CF3,OCF3, OCHF2,SCF3, SCN, ethinyl, vinyl, or diﬂuorovinyl groups.

6.5 Alkylating Agents

The vesicant properties of sulfur mustard (bis(2-chloroethyl)sulﬁde), used in World War I for chemical warfare, were already known in 1887. This compound is strongly cytotoxic, in particular to highly proliferative tissue, such as lymphoid tissue, bone marrow, and the intestine. Between the wars, the corresponding nitrogen mustards were shown to be similarly toxic, and in 1942, clinical trials were started to evaluate these alkylating agents in the treatment of various types of cancer. At present, mainly nitrogen mustards, alkyl sulfonates, aziridines, nitrosoureas (Chapter 12), and triazenes (Chapter 10) are used as antineoplastic alkylants (Table 6.1). One common feature of the alkylating agents for cancer therapy is their ability to mediate two alkylations and thereby crosslink two DNA molecules or DNA with a protein. Such a modiﬁcation prevents both the replication of DNA and the biosynthesis of proteins. Reference 55

Reference

1. (a) Hagmann, W.K. (2008) The many roles for fluorine in medicinal chemistry. J. Med. Chem., 51, 4359–4369; (b) Park, B.K., Kitteringham, N.R., and O’Neill, P.M. (2001) Metabolism of fluorine-containing drugs. Annu. Rev. Pharmacol. Toxicol., 41, 443–470; (c) Patani, G.A. and LaVoie, E.J. (1996) Bioisosterism: a rational approach in drug design. Chem. Rev., 96, 3147–3176; (d) Park, B.K. and Kitteringham, N.R. (1994) Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metabol. Rev., 26, 605–643.

Table 6.1 Alkylating agents and alkyl chlorides. V in l kg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ . ± . . ± . t 2 2 6 0 5h V 1 0 0 2 BUSULFAN O O F 70% CL/F 4.5±0.9 Antineoplastic; Metabolism: S O pb 3–15% Mwt 246.3 conjugation with glutathione, then O S ur 0.5–3.0% PSA 104 A˚ 2 conversion to O O log P −0.56 tetrahydrothiophene S-oxide, sulfolane, and 3-hydroxysulfolane

1/ < t 2 1min V – CHLORMETHINE, Cl Cl F – CL – MECHLORETHAMINE N pb – Mwt 156.1 Antineoplastic for iv ur 0% PSA 3.24 A˚ 2 administration log P 0.91

1/ . ± . . ± . t 2 7 5 4 0h V 0 9 0 6 CYCLOPHOSPHAMIDE F 74±22% CL 1.3±0.5 Antineoplastic, Cl pb 13% Mwt 261.1 immunosuppressant; activation O H N N ur 6.5±4.3% PSA 51.4 A˚ 2 by hepatic metabolism; P log P 0.73 Metabolism: O Cl N-dealkylation, hydroxylation at CH2NH, then oxidation to lactam and ring opening to carboxylic acid

1/ t 2 4–10 h V 0.4–0.6 IFOSFAMIDE F 100% CL 0.8–2.3 Antineoplastic, crosses bbb pb 20% Mwt 261.1 Metabolism: hydroxylation of ring Cl 2 H O ur 15% PSA 51.4 A˚ CH2N to active form of drug, N N P log P 0.76 followed by ring-opening and β O -elimination to acrolein; Cl hydroxylation of exocyclic CH2N followed by hydrolysis to chloroacetaldehyde

1/ t 2 1–2 h V – THIOTEPA S F – CL 19 Antineoplastic; Metabolite: N P N pb – Mwt 189.2 phosphoramide (tepa, replacement N < 2 1/ ur 10% PSA 50.9 A˚ of S by O; t 2 3–24 h) log P 0.53 (continued overleaf ) 56 6 Halides

t1/ 1.3±0.9h V 0.29±0.21 CHLORAMBUCIL Cl 2 F 87±20% CL 2.6±0.9 Antineoplastic N pb 99% Mwt 304.2 Metabolism: ur <1% PSA 40.5 A˚ 2 oxidative degradation to arylacetic CO2H Cl log P 2.61 acid, substitution of Cl by OH

1/ t 2 0.5 h V 0.24–0.32 BENDAMUSTINE Cl F – CL 7.5 Antineoplastic pb >95% Mwt 358.3 Metabolism: N N ur 10–45% PSA 58.4 A˚ 2 substitution of Cl by OH, CO2H Cl N log P 2.38 N-demethylation, conjugation with glutathione, hydroxylation of propylene

1/ . ± . . ± . t 2 1 4 0 2h V 0 5 0 2 MELPHALAN Cl CO2H F 71±23% CL 5.2±2.9 Antineoplastic NH pb 90±5% Mwt 305.2 Metabolism: N 2 ur 12±7% PSA 66.6 A˚ 2 sequential displacement of Cl log P 0.54 chloride by hydroxide

1/ OH t 2 9–23 h V 0.11 ESTRAMUSTINE F 44–75% CL 0.9–1.1 Antineoplastic H pb 99% Mwt 440.4 Metabolism: Cl O ur – PSA 49.8 A˚ 2 oxidation to ketone, hydrolysis H H log P 5.75 of carbamate; oral prodrug: N O phosphoric acid ester Cl

1/ t 2 18–159 d V – MITOTANE Cl Cl F 40% CL – Antiadrenal agent, antineoplastic; pb – Mwt 320.0 blocks 11β-hydroxylation of ur 0% PSA 0.0 A˚ 2 adrenocorticoid precursors log P 5.41 Metabolite: diarylacetic acid, Cl Cl dehydrogenation to 1,1-diaryl-2,2-dichloroethylene

1/ ∗ Cl t 2 21 h V 8 LINDANE ∗ Cl Cl F –CL– sheep pb 91% Mwt 290.8 Insecticide ur – PSA 0.0 A˚ 2 Metabolites: Cl Cl log P 3.82 1,2,4-trichlorobenzene, di- and Cl trichlorophenols 57

1/ ± ± t 2 5 2h V 8 5 CLOMETHIAZOLE F 30±10% CL 18±7 Sedative, hypnotic, anticonvulsant S Cl pb 63±2% Mwt 161.7 Metabolism: hydroxylation to ur <1% PSA 41.1 A˚ 2 1-hydroxy-2-chloroethyl, then N log P 1.71 dehydrohalogenation to 5-acetyl-4-methylthiazole, then reduction to alcohol

1/ Cl t 2 144 h V 8.2 TETRACHLOROETHYLENE, Cl F High CL – PERC Cl pb – Mwt 165.8 Dry cleaning solvent, anthelmintic Cl ur <4% PSA 0.0 A˚ 2 Metabolites: trichloroacetic acid log P 3.07 t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area. 58

7 Azides

At present, only few azido-group-containing drugs are on the market, for example, zidovudine and azidocillin (Scheme 7.1). Zidovudine is a nucleoside mimetic, the azido group replacing a hydroxyl group of 2-deoxythymidine. Azidocillin is an older β-lactam antibiotic, closely related to ampicillin and benzylpenicillin, which was developed in the late 1960s.

O H N N 3 H H HO O N S O N O N O N3 CO2H Zidovudine Azidocillin t1/2 1.1 h, F 63% t1/2 0.6–1.1 h, F 57–64%

Scheme 7.1 Azides as drugs.

Azides are chemically reactive, and may act as electrophilic aminating reagents under acidic conditions, similar to hydroxylamines. High doses of organic azides can therefore cause adverse drug reactions (see Section 2.6). One of the various metabolic transformations of zidovudine and azidocillin is the reduction of the azido group to an amino group.

8 Nitro Compounds

Most drugs with nitro groups are nitroarenes, nitroheteroarenes, or nitroethylenes. Nitroalkanes have not been used as drugs and may be metabolically too unstable. The nitro group has a strong dipole moment, which leads to higher boiling and melting points of nitroarenes when compared to chloro- or bromoarenes (Scheme 8.1). When considering intermolecular attractive forces, nitroarenes are more closely related to acetophenones or benzoic esters than to haloarenes.

O O NO CN Cl Br 2 OMe

Cl Nitrobenzene Acetophenone Methyl benzoate Benzonitrile Dichlorobenzene Bromobenzene bp 211 °C bp 203 °C bp 200 °C bp 191 °C bp 181 °C bp 156 °C mp 6 °C mp 21 °C mp –12 °C mp –13 °C mp –17 °C mp –31 °C log P 1.92 log P 1.67 log P 2.12 log P 1.58 log P 3.44 log P 2.94

Scheme 8.1 Properties of nitrobenzene and other substituted arenes.

Nitroarenes are rather lipophilic and barely soluble in water. Further, lipophilic compounds with separated charges in their Lewis structures include diazoalkanes, nitrones, azides, and phosphorus- or sulfur-derived ylides. In their noncovalent interactions with proteins, nitroarenes behave as halo- or alkylarenes. For instance, dihydropyridine-based calcium channel antagonists (antihypertensives) often contain nitrophenyl groups, which may be replaced by 1,2-dichlorophenyl without altering the target selectivity (Scheme 8.2). In benzodiazepines, replacement of the 7-chlorine atom by a nitro group is also tolerated without affecting their hypnotic and sedative properties or their ability to cross the blood–brain barrier (bbb). The same is the case for the two anticoagulants acenocoumarol and warfarin.

NO2 Cl

NO2 Cl MeO2CCO2Me MeO2CCO2Et MeO2C CO2Et

N N N H H H Nifedipine Nitrendipine Felodipine t1/2 2.5 h, F 50% t1/2 4 h, F 14–55% t1/2 14 h, F 15%

H O H O O O N N N N

O2N N Cl N O2N N Cl N F F

Nitrazepam Nordazepam Flunitrazepam Fludiazepam t1/2 26 h, F 78% t1/2 73 h, F 99% t1/2 15 h, F 85% t1/2 23–48 h O O

OH OH

O O NO2 O O Acenocoumarol Warfarin t1/2 8–11 h, F 60% t1/2 37 h, F 39%

Scheme 8.2 Impact on pharmacokinetics (PK) of the nitro group.

8.1 Metabolism

The most common metabolic transformation of nitroarenes is reduction to anilines by bacteria in the bowel, followed by N-acetylation. Potentially toxic metabolites include nitrosoarenes and N-arylhydroxylamines. The rate of reduction depends on the electron density at the nitroarene and is usually higher at electron-poor nitroarenes. In all the examples in Scheme 8.3, the nitro group undergoes metabolic reduction.

Cl O O O CF3 HO Cl NH O2N N N HN NH OH N NO2 O N O2N O

O O2N OH N Nilutamide Chloramphenicol Secnidazole Nitrofurantoin t1/2 38–59 h, F 80–90% t1/2 4 h, F 83% t1/2 14–20 h, F 99% t1/2 1 h, F 90%

Scheme 8.3 Nitro group containing drugs. 8.1 Metabolism 61

The antibacterial and antiprotozoal activity of nitroazoles and nitrofurans, such as secnidazole and nitrofurantoin, depends on their reduction to radical anions by the target organism. Nitro groups that are reduced quickly may serve as prodrugs. Netobimin, for instance, is metabolized by nitro group reduction to albendazole and its active metabolite albendazole sulfoxide (Scheme 8.4).

H MeO N N reduction and SO H O O 3 benzimidazole first-pass MeO S O HN S formation in vivo metabolism N HN – taurine (S-oxidation) N O2N H Netobimin Albendazole sulfoxide t1/2 8–12 h

Scheme 8.4 Metabolism of netobimin. 62

9 Azo Compounds

Paul Ehrlich, working at the Institute for Experimental Therapeutics in Frankfurt am Main, tested the dye methylene blue as potential analgesic because of its high afﬁnity to nerves. In 1891, however, he cured two cases of mild malaria by treatment with methylene blue. Hundreds of dyes were then tested for antibacterial and antiprotozoal activity by Ehrlich and others, which led to the discovery of a number of useful drugs, among others of prontosil by Gerhard Domagk, Fritz Mietzsch, and Josef Klarer in 1932. This substance turned out to be a prodrug of sulfanilamide, a competitive antagonist of 4-aminobenzoic acid, and the active principle of prontosil (Scheme 9.1). The azo group is cleaved in the gut by intestinal bacteria.

O O S O O NH 2 NH S N in vivo 2 NH N + 2

H2N NH2 H2N H2N NH2 Prontosil 1,2,4-Triaminobenzene Sulfanilamide Sulfamidochrysoidine

Scheme 9.1 Metabolism of prontosil. O CO H CO H 2 N 2 H HO C N HO C N 2 N OH 2 N

HO Olsalazine HO Balsalazide − t1/2 1 h t1/2 2 3 h F < 5% F < 1% O O S N N N H N HO C N 2 N H2N N NH2 HO Sulfasalazine Phenazopyridine − t1/2 1 14 h t1/2 1 h F < 20% F > 60%

Scheme 9.2 Azo compounds as drugs.

Other drugs containing azo groups are shown in Scheme 9.2. These also undergo reductive cleavage in the intestine and are prodrugs for various analgesics and antibacterials. 64

10 Triazenes

Triazenes result from the reversible addition of secondary amines to diazonium salts. This reaction proceeds readily under basic conditions, but acids quickly regenerate the starting materials. With primary aliphatic amines, diazotization followed by carbocation formation may occur (Scheme 10.1).

N Base N N N + HN N Acid

N H N N N R + N H2N R

H N N R NH N 2 N + N R

Scheme 10.1 Formation and decomposition of triazenes.

The antineoplastics dacarbazine and CB 10-277 (Scheme 10.2) have to be administered intravenously and are activated by N-demethylation in the liver. The resulting N-monomethyltriazenes decompose by the mechanism shown above to yield diazomethane or a methyl diazonium salt, which are exceedingly strong methylating agents. Temozolomide is similarly metabolized to an N-monomethyltriazene by urea hydrolysis. All these drugs are used to treat aggressive tumors (melanoma, Hodgkin’s disease, and malignant brain tumors). Other drugs that are metabolized into methylating reagents include procarbazine and altretamine.

O N N N N N N N N N N N KO NH N 2 N NH2 H O O O CB 10-277 Dacarbazine Temozolomide t1/2 2.5 h (iv) t1/2 5 h (iv) t1/2 1.8 h, F 96%

Scheme 10.2 Antineoplastic triazenes. 66

11 Nitrates and Nitrites

The vasodilating and antianginal properties of alkyl nitrates and nitrites were already discovered in the 1860 s and used since then for the treatment of angina pectoris. Nitrates and nitrites undergo reductive hydrolysis in vivo to yield the parent alcohol and nitric oxide (NO). The latter triggers the biological effect of these substances. The half-life at which nitrates or nitrites generate nitric oxide ranges from a few minutes to several hours (Scheme 11.1). Lipophilic nitrates are hydrolyzed faster and have lower bioavailabilities than hydrophilic nitrates.

O NO NO O 2 O 2 O in vivo N NO2 O O O OH H O2N NO2 O2N N Nicorandil Nitroglycerin Glycerin dinitrate t1/2 1–2 h t1/2 2.3 min t1/2 40 min F 75% F < 1% (38% sublingual)

NO2 H O H OH O in vivo O O O O O O O N N O H O H O2N O2N Isosorbide dinitrate Isosorbide mononitrate Isoamyl nitrite Isobutyl nitrite t 1/2 1 h t1/2 5 h t1/2 1.4 min (rat) F 22% F 93% F 43% (rat, inhaled)

Scheme 11.1 Alkyl nitrates and nitrites as drugs.

Derivatives of N-nitrosamines, such as the antineoplastic N-nitrosourea carmustine, may also yield nitric oxide in vivo. However, the main metabolic pathway of N-nitrosoureas is their decomposition to alkyl diazonium salts and eventually carbocations.

Further Reading

Sneader, W. (1999) Organic nitrates. Drug News Perspect., 12, 58–63. 68

12 N-Nitroso Compounds

Various N-(2-chloroethyl)-N-nitrosoureas are being used as oral or parenteral drugs for the treatment of aggressive neoplasms, such as brain or pancreatic tumors, or melanoma (Table 12.1). Nitrosoureas are readily cleaved by nucleophiles and are hence rather unstable. Nucleophilic cleavage yields N-nitrosamines, which quickly eliminate water and nitrogen to yield strongly alkylating carbocations (Scheme 12.1). The resulting chloroethylated nucleophiles may alkylate additional nucleophilic functional groups and thus cross-link proteins or nucleic acids. As most other antineoplastics, all nitrosoureas are carcinogenic and mutagenic.

O O Cl R NuH Cl R N N NH+ Nu N H H N N O O

Cl + H+, −H O N 2 Cl NuH Cl N Nu N N OH

Scheme 12.1 Decomposition of nitrosoureas.

− Table 12.1 N-Nitrosoureas. V inlkg−1;CLinmlmin−1 kg 1; Mwt in g mol−1.

1/ . ∗ t 2 1.5 h V 1 7 LOMUSTINE F 100%∗ CL – Antineoplastic, crosses bbb, O pb 50%∗ Mwt 233.7 carcinogenic, mutagenic Cl N N ur – PSA 61.8 A˚ 2 Metabolism: hydroxylation of H N log P 2.72 cyclohexyl group (4-cis and O 1/ trans-hydroxy; t 2 16–48 h) ∗metabolites on oral dosing of drug.

t1/ 1.5±2.0h V 3.3±1.7 CARMUSTINE, BCNU O 2 F –CL56±56 Antineoplastic, carcinogenic, Cl Cl N N pb 77% Mwt 214.1 mutagenic, crosses bbb H ˚ 2 N ur – PSA 61.8 A O log P 1.38

1/ t 2 4min(iv) V – CYSTEMUSTINE O O O F Low CL – Antineoplastic S Cl N N pb – Mwt 257.7 H 2 N ur – PSA 104 A˚ O log P −0.17

1/ ± t 2 57 22 min V – TAUROMUSTINE O O O F 26% (dog) CL – Antineoplastic S Cl N N N pb – Mwt 286.7 H 2 N ur – PSA 108 A˚ O log P 0.77

1/ ± ∗ O t 2 29 12 min V –FOTEMUSTINE ± ∗ EtO Cl F –CL2817 iv P N N pb – Mwt 315.7 Antineoplastic H EtO O N ur – PSA 107 A˚ 2 O log P 1.37

1/ O OH t 2 7min(iv) V – CHLOROZOTOCIN HO O F – CL – Antineoplastic Cl pb – Mwt 313.7 HO N N H ur – PSA 160 A˚ 2 OH N O log P −0.71

1/ ∗ O OH t 2 15 min V 0.7 STREPTOZOTOCIN HO O F Low CL – ∗iv HO N N pb – Mwt 265.2 Antineoplastic, does not cross H ∗ ˚ 2 OH N ur 10–20% PSA 160 A bbb O log P −1.33

1/ ∗ O t 2 0.2–1.1 h V 1.6 NIMUSTINE, ACNU ∗ Cl F –CL35iv N N N pb – Mwt 272.7 Antineoplastic H N ur – PSA 114 A˚ 2 N NH2 O log P 0.25

13 N-Oxides

Pyridine or pyrimidine N-oxides are common metabolites of pyridines and pyrimidines. As other metabolites, some N-oxides also have made their way to the market and are being used as oral drugs. Despite their high dipole moments, these compounds are orally bioavailable (Scheme 13.1). Typical metabolic transformations include O-sulfation, O-glucuronidation, and reductive cleavage of the N–O bond.

O N O N N OH N N

N H2N N NH2 N NH2 O O O

Acipimox Minoxidil Tirapazamine t1/2 12–14 h t1/2 3.1 h t1/2 0.8 h (iv) F 100% F 90% F 75%

Scheme 13.1 N-Oxides as drugs.

14 Alcohols

Hydroxyl groups enhance the solubility and rate of renal excretion of a drug. The lower affinity to liver enzymes may also reduce the first-pass effect and enhance the oral availability of a hydroxylated lead. On the other hand, a high hydrophilicity and large polar surface area can accelerate renal excretion and compromise the ability of a compound to be completely absorbed from the small intestine and to cross membranes, such as the blood–brain barrier (bbb), unless the molecule is very small. Thus, while ethanol (t1/2 0.24 h, F 80%) is well absorbed and even crosses the bbb, polyols such as sorbitol, mannitol, or glycerol have poor oral bioavailabilities. Carbohydrates are usually absorbed by a compound-specific active transport mechanism. Comparison of fenpiprane, zimeldine, and chlorpheniramine with the tertiary alcohols pridinol, procyclidine, and pirmenol shows that the hydroxyl group can lead to higher oral availability by curbing first-pass metabolism (Scheme 14.1).

Br Cl

N N N

N N

Fenpiprane Zimeldine Chlorpheniramine active only on t1/2 5 h, F 27% t1/2 20 h, F 41% parenteral administration V 3.2 l kg−1, log P 3.07 V 3.2 l kg−1, log P 2.97

OH OH OH N N N

Pridinol Procyclidine Pirmenol t 14 h, F 77% t 12 h, F 75% t 6–18 h, F 80–90% 1/2 1/2 − 1/2 − log P 3.35 V 0.74 l kg 1, log P 3.86 V 1.5 l kg 1, log P 3.57

Scheme 14.1 Effect of tertiary hydroxyl groups on pharmacokinetics (PK).

14.1 Metabolism

Many hydrophilic alcohols, such as oxiracetam, mannitol, meglumine, miglitol, the bronchodilator salbutamol, or the contrast agent iopamidol, are barely metabolized, but mostly excreted unchanged in the urine (Scheme 14.2).

HO OH HO OH HN O O H HO OH N H2N N HO I I N O H O HO HO N HO N OH OH H O I OH HO Oxiracetam Miglitol Salbutamol Iopamidol t1/2 3–8 h, F 75% t1/2 2–4 h, F 60–90% t1/2 3–5 h, F 43–50% t1/2 23 h, F low renal excretion renal excretion renal excretion renal excretion unchanged 50–84% unchanged 100% unchanged 51–64% unchanged 87% (iv)

Scheme 14.2 Alcohols as drugs.

Larger, more lipophilic alcohols may, however, undergo some sort of metabolism, either to further facilitate their renal excretion or to degrade the molecule into smaller fragments. Primary and secondary alkanols can be oxidized by alcohol dehydrogenase to aldehydes or ketones, which can be further oxidized to carboxylic acids. The oxidation of secondary alcohols to ketones is reversible, and with some substrates, for instance haloperidol, both the ketone and the alcohol can be detected in plasma (Scheme 14.3).

F F OH OH O OH N N

F F Haloperidol metabolite t1/2 18 h, F 60% t1/2 67 h

Scheme 14.3 Reversible reduction of haloperidol.

Because the oxidation of primary, purely aliphatic alcohols is usually fast, few drugs contain this functional group. Alcohols with a heteroatom in β-orγ-position, however, are more resistant to oxidation, as illustrated by the examples shown in Scheme 14.4. Secnidazole undergoes hydroxylation at the vinylic methyl group in vivo, chloramphenicol is mainly converted into an inactive glucuronide, and the main metabolite of ciramadol is the phenolic glucuronide (Table 14.1). 14.1 Metabolism 73

Cl HO O HO Cl OH O2N NH OH N N H N O2N OH Secnidazol Chloramphenicol Ciramadol t1/2 14–20 h, F 99% t1/2 4 h, F 83% t1/2 5 h, F 82%

OH NH2 O O HO OH Febuprol Fingolimod t1/2 2 d, F > 90% t1/2 7 d, F 95%

Scheme 14.4 Drugs containing hydroxyl groups.

Drugs with carbohydrate substructures may be metabolized by phosphorylation. This is often the case for antiviral or antineoplastic nucleoside analogs, which are phosphorylated in vivo to the corresponding nucleotides and then incorporated into DNA (Scheme 14.5).

O HO N HO N NH2 O N N O

F N NH HO F HO NH2 Gemcitabine Entecavir t1/2 0.2–0.4 h; F 10% t1/2 128–149 h; F 70% metabolism: O-phosphorylation metabolism: O-phosphorylation

Scheme 14.5 Carbohydrate analogs as drugs.

The oxidation of alcohols may be prevented either by introducing ﬂuorine or other electron-withdrawing atoms or groups at the β-position (to prevent α-hydride abstraction) or by choosing a tertiary alcohol instead. Tertiary alcohols can undergo hydroxylation to 1,2-diols, as in the case of the α1-adrenergic antagonist trimazosin (Scheme 14.6).

O O OH OH OMe N O OMe N O MeO N N MeO N N OH N N MeO MeO Trimazosin Hydroxytrimazosin NH t 3 h, F 63% NH 2 1/2 2 t1/2 1.6 h

Scheme 14.6 Metabolism of trimazosin. 74 14 Alcohols

Table 14.1 Aliphatic alcohols, carbohydrates, and related compounds. V inlkg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ . ± . . ± . t 2 0 2 0 1h V 0 54 0 05 ETHANOL F 80% CL – Recreational drug, hypnotic OH pb – Mwt 46.1 ur <3% PSA 20.2 A˚ 2 log P −0.18

1/ t 2 4–12 h V 0.9 TRICHLOROETHANOL Cl F – CL – Metabolite of chloral hydrate Cl OH pb 70–80% Mwt 149.4 Cl ur – PSA 20.2 A˚ 2 log P 0.97

t1/ 8–11 h V 0.6 CHLORAL HYDRATE Cl 2 Cl F – CL – Hypnotic, sedative OH Cl pb – Mwt 165.4 Metabolism: reduction to OH ur 0% PSA 40.5 A˚ 2 trichloroethanol, log P 0.99 then glucuronidation

t1/ 2.3–2.5 h V – METRIFONATE Cl O 2 Cl OMe F – CL 8.2–9.3 Anthelmintic P Cl OMe pb – Mwt 257.4 Metabolism: rearrangement OH ur 2% PSA 65.6 A˚ 2 to dichlorvos (2,2-dichlorovinyl log P 0.49 dimethyl phosphate)

1/ t 2 10–20 h V 3.5 ETHCHLORVYNOL OH F – CL 1.7–2.0 Hypnotic, anticonvulsant, Cl pb 35–50% Mwt 144.6 muscle relaxant ur Negligible PSA 20.2 A˚ 2 log P 1.19

t1/ 1h∗ V – MENTHOL OH 2 F –CL–∗glucuronide pb – Mwt 156.3 No menthol detectable in ur 46–57%∗ PSA 20.2 A˚ 2 plasma after oral dosing log P 3.22

t1/ 21±2h V 41±18 FLUMECINOL OH 2 F –CL26±9 Hepatic enzyme inducer CF 3 pb – Mwt 280.3 Metabolism: phenyl and ethyl ur 0% PSA 20.2 A˚ 2 hydroxylation, then conjugation log P 4.21

1/ t 2 4–14 h V 1 STIRIPENTOL OH F 21±9% CL 6–29 Antiepileptic, racemic pb 99% Mwt 234.3 Metabolism: O-glucuronidation, O ur Negligible PSA 38.7 A˚ 2 tert-butyl hydroxylation, O log P 3.78 isomerization of allyl alcohol to propanone, acetal hydrolysis, then catechol O-methylation 75

t1/ 1h V – IDROCILAMIDE O 2 F 30% CL – Muscle relaxant OH N pb – Mwt 191.2 H ur 1% PSA 49.3 A˚ 2 log P 0.44

1/ t 2 41 min (rat) V 2.1 (rat) DITAZOL F – CL 34.5 (rat) Antiinﬂammatory pb – Mwt 324.4 Metabolites: N-desalkyl, ˚ 2 , O ur – PSA 69.7 A N N-bisdesalkyl, hydroxy, log P 2.35 benzil, hydroxybenzil OH N N OH

t1/ 2.9 h V 0.19 IOHEXOL OH H 2 HO N O F – CL 2 X-ray contrast agent; triiodobenzoic pb 0% Mwt 821.1 acid is too highly plasma bound I I ˚ 2 H OH ur 90% PSA 200 A and too toxic. This toxicity is N log P −2.92 reduced by conversion to the more N hydrophilic iohexol. HO O I OH OH O

1/ OH t 2 1.8 h V 0.28 IOMEPROL H HO N O F – CL 1.6–1.7 X-ray contrast agent pb – Mwt 777.1 I I ˚ 2 O ur 87–92% PSA 180 A H − . N OH log P 2 93 N HO O I OH

1/ OH t 2 4.6 h V 0.2 IOPROMIDE HO N O F – CL 1.4 X-ray contrast agent pb 1% Mwt 791.1 I I ur 85% PSA 169 A˚ 2 H O N OCH log P −2.66 N 3 HO O I OH

1/ t 2 2.2 h V 0.28 IODIXANOL OH H F – CL 1.7 X-ray contrast agent HO N O pb – Mwt 1550.2 ˚ 2 I I ur 97% PSA 339 A H log P −4.07 N N CH HO O I OH OH O 2

(continued overleaf ) 76 14 Alcohols

t1/ 2–3 h V 0.2–0.3 IOPAMIDOL HO OH 2 F – CL 1.9 X-ray contrast agent HN O pb 0% Mwt 777.1 I I ur 86% PSA 188 A˚ 2 O H log P −2.55 N HO N H O I OH HO

t1/ 2.7 h V 0.2 IOSIMIDE HO 2 N O F – CL – X-ray contrast agent HO OH pb – Mwt 849.2 I I ˚ 2 HO OH ur 87% PSA 182 A − . N N log P 3 02 HO O I O

1/ t 2 3–9 h V 0.5–0.8 ETHYLENE GLYCOL F 92–100% CL – Antifreezer OH HO pb – Mwt 62.1 Metabolism: oxidation to ur 20% PSA 40.5 A˚ 2 hydroxyacetaldehyde, glycolic acid, log P −1.36 and glyoxylic acid

1/ t 2 0.5–1.2 h V 0.2–0.3 GLYCEROL OH F >80% CL 2 Osmotic diuretic HO OH pb – Mwt 92.1 ur 7–14% PSA 60.7 A˚ 2 log P −1.85

1/ ± . ± . t 2 2 1min V 3 3 1 2 NITROGLYCERIN NO < ∗ ± ∗ ± O 2 F 1% CL 230 90 sublingual: 38 26% O O pb – Mwt 227.1 Antianginal 2 O2N NO2 ur <1% PSA 165 A˚ Metabolism: denitration 1/ log P 2.15 (to glycerol dinitrate, t 2 40 min)

1/ OH t 2 3–4 h V 1.3 CHLORPHENESIN O OH F – CL – Topical antifungal pb – Mwt 202.6 ur 0% PSA 49.7 A˚ 2 Cl log P 1.71

1/ OH t 2 1h V 1 GUAIFENESIN O OH F High CL – Expectorant pb 37% Mwt 198.2 Metabolism: oxidation of ur – PSA 58.9 A˚ 2 primary alcohol to CO H OMe 2 log P 0.46 77

1/ OH t 2 2d V – FEBUPROL > O O F 90% CL – Choleretic pb 60–70% Mwt 224.3 Metabolites: 4-hydroxyphenyl 2 1/ ur Low PSA 38.7 A˚ (t 2 3 h), glucuronide log P 2.91

1/ t 2 4h(iv) V 0.4 POLIDOCANOL O OH F – CL 3 Local anesthetic, antipruritic, O 8 pb 64% Mwt 582.8 spermicide ur – PSA 103.3 A˚ 2 Metabolism: log P 3.42 oxidative degradation of alkyl chain

t1/ 7±2d V 18±4FINGOLIMOD NH 2 2 F 95% CL 1.6 Immunomodulator HO pb 99.7% Mwt 307.5 Active metabolite: phosphate OH ur – PSA 66.5 A˚ 2 log P 4.2

t1/ 0.3–1.7 h V 0.5 MANNITOL OH OH 2 F 7–20% CL 7 Osmotic diuretic OH HO pb 0% Mwt 182.2 ˚ 2 OH OH ur 80–90% PSA 121 A log P −3.26

1/ ∗ t 2 0.2–0.6 h V 0.2 SORBITOL OH OH F Low CL – ∗iv OH HO pb 0% Mwt 182.2 Sweetener, laxative < ˚ 2 OH OH ur 3% PSA 121 A log P −3.26

1/ t 2 2.6 h V –MEGLUMINE OH OH F – CL – Drug excipient OH N pb – Mwt 195.2 H ˚ 2 OH OH ur 91% PSA 113 A log P −2.51

1/ t 2 4–12 h V – ASCORBIC ACID, VITAMIN C HO ∗ ∗ H F 100% CL 1.1 for 200 mg dose O O pb 24% Mwt 176.1 Larger doses: lower F, higher ur HO ur 0% PSA 107 A˚ 2 Metabolites: 2-sulfate, − . HO OH log P 2 41 dehydroascorbic acid (diketone), oxalic acid

1/ HO t 2 2–4 h V 0.28 MIGLITOL F 60–90% CL 1.7 Antidiabetic; no metabolism HO OH pb <4% Mwt 207.2 N ur 100% PSA 104 A˚ 2 HO log P −2.21 OH

(continued overleaf ) 78 14 Alcohols

1/ HO t 2 6–7 h V 0.7–1.3 MIGLUSTAT F 97% CL 3.5 Antidiabetic HO pb 0% Mwt 219.3 Metabolism: glucuronidation N ur 50% PSA 84.2 A˚ 2 HO log P 0.03 OH

1/ t 2 14 h V – ISOFAGOMINE HO NH F – CL – Treatment of Gaucher’s disease HO pb – Mwt 147.2 ˚ 2 OH ur – PSA 72.7 A log P −1.80

1/ . ± . . ± . HO t 2 5 1 1 5h V 1 3 0 2 LINCOMYCIN O F 25±5% CL 2.1±0.5 Antibacterial H ± N O SMe pb 85 2% Mwt 406.5 Metabolism: oxidation to N 2 H ur 14±6% PSA 148 A˚ sulfoxide, N-demethylation HO OH log P 0.72 OH

1/ . ± . . ± . Cl t 2 2 9 0 7h V 1 1 0 3 CLINDAMYCIN O F 87% CL 4.7±1.3 Bacteriostatic H O SMe pb 93.6±0.2% Mwt 425.0 Metabolites: sulfoxide, N N H ur 13% PSA 128 A˚ 2 N-desmethyl, glucuronide HO OH log P 1.75 OH

1/ ± . ± . t 2 4 2h V 0 94 0 06 CHLORAMPHENICOL OH NO2 O F 83±8% CL 2.4±0.2 Antibacterial, antirickettsial, Cl pb 53±5% Mwt 323.1 carcinogenic N H ur 25±15% PSA 115 A˚ 2 Metabolism: reduction of Cl OH log P 1.10 nitro group by intestinal bacteria

1/ O O t 2 1.5–2.4 h V 0.75 THIAMPHENICOL ∗ ∗ OH S F 60% CL – calves O pb 10–20% Mwt 356.2 Antibacterial Cl ˚ 2 N ur 60% PSA 112 A Metabolism: glucuronidation H − . Cl OH log P 0 27

1/ HO t 2 2h V –LACTULOSE OH F 0.4–2.0% CL – Laxative HO pb – Mwt 342.3 O O 2 OH ur <3% PSA 197 A˚ HO O − . OH log P 2 97 OH OH 79

1/ HO t 2 3–23 h V – SUCRALOSE, SPLENDA F 11–40% CL – Artiﬁcial sweetener Cl HO OH pb – Mwt 397.6 Metabolism: glucuronidation O Cl ur 6–18% PSA 129 A˚ 2 HO O O log P 0.23 OH Cl

1/ Cl OEt t 2 17 h V 0.8 (dog) DAPAGLIFLOZIN F >75% CL 1.5 (dog) Glucose transporter inhibitor, O HO pb 96% Mwt 408.9 antidiabetic ur <2.5% PSA 99.4 A˚ 2 Metabolism: glucuronidation, HO OH OH log P 4.42 O-deethylation, hydroxylation

t1/ 21±4h V/F 0.045 AURANOFIN O 2 F 20±5% CL/F 0.025±0.016 Antiarthritic O S P O Au pb 60% Mwt 678.5 Metabolism: deacetylation ur 15% PSA 114.5 A˚ 2 O O log P 0.81 O O O O

t1/ 1–3 h V 0.13 SPECTINOMYCIN HN O 2 H HO F 10% (pig) CL 0.99 ∗iv HO O pb Low Mwt 332.4 Antibacterial, ur 70–100%∗ PSA 130 A˚ 2 no metabolism N O O H H H log P 0.75 HO

t1/ 11 h (iv) V 0.7 TROSPECTOMYCIN HN O 2 H HO F 7% CL 1.7 Antibacterial HO O pb – Mwt 374.4 ur – PSA 130 A˚ 2 N O O H H H log P 2.27 HO

1/ O t 2 2–3 h (im) V 0.16 AMIKACIN F – CL 1.1 Antibacterial for im or H2N NH OH pb 0–11% Mwt 585.6 iv administration O NH HO 2 ur 98% (im) PSA 332 A˚ 2 For review, see: Busscher, G.F., O log P −5.26 Rutjes, F.P.J.T., van Delft, F.L. H N O OH 2 2-Deoxystreptamine: central O O H H2N OH scaffold of aminoglycoside HO OH antibiotics. Chem. Rev. 2005, 105 OH , 775–791.

(continued overleaf ) 80 14 Alcohols

1/ O t 2 24 h (iv) V 0.32 ISEPAMICIN F – CL 1.3 Aminoglycoside antibiotic H2N NH OH H pb 5% Mwt 569.6 O O N 2 H ur 75% (im) PSA 298 A˚ O OH log P −4.68 H2N O O O H H2N HO OH OH

1/ NH H t 2 2.5 h (iv) V 0.25 RIBOSTAMYCIN 2 OH O F – CL 1.5 Aminoglycoside antibiotic O pb – Mwt 454.5 OH 2 H N O ur – PSA 262 A˚ 2 − . O O OH log P 3 95 H2N

HO NH2 OH

1/ t 2 2.4 h (iv) V 0.13 DIBEKACIN H2N OH F – CL 0.80 Antibacterial H2N NH2 OH O O pb – Mwt 451.5 ur High PSA 248 A˚ 2 O O NH2 log P −3.58 NH2 OH OH

1/ . ± . t 2 2h V 0 33 0 08 TOBRAMYCIN H2N OH NH F Low CL 0.98 Antibacterial HO H2N 2 OH O O pb <10% Mwt 467.5 ur 60% PSA 268 A˚ 2 O O NH2 log P −4.22 OH NH2 OH

1/ . ± . . ± . H N OH t 2 2 1 0 2h V 0 26 0 05 KANAMYCIN B 2 . ± . ∗ NH F Low CL 1 4 0 2 iv HO H2N 2 OH O O pb 0% Mwt 483.5 Antibacterial ur 90%∗ PSA 288 A˚ 2 HO O O NH 2 log P −4.02 NH2 OH OH

1/ . ± . NH t 2 2–5 h V 0 3 0 1GENTAMICIN 2 ∗ H2N NH2 OH F Low CL 0.82 iv O O pb <10% Mwt 449.6 Antibacterial ∗ 2 O O NH ur >90% PSA 213.7 A˚ log P −4.89 NH2 OH OH 81

1/ . ± . t 2 2–4 h V 0 20 0 02 NETILMICIN H2N F 0% CL 1.3±0.2 ∗iv H N NH OH 2 < O O pb 10% Mwt 475.6 Antibacterial ur 85±5%∗ PSA 200 A˚ 2 O O NH log P −1.84 NH2 OH OH

1/ t 2 2–3 h V/F 0.4 PAROMOMYCIN NH2 H OH O F Negligible CL/F 1.8 Antibacterial O pb – Mwt 615.6 O NH2 ˚ 2 HO H2N O ur High PSA 347 A O O OH O OH log P −5.80

H2N OH HO NH2 OH

1/ OH t 2 3–9 h V 0.32 ACARBOSE HO F 0.5–1.7% CL 143 α-Glucosidase, glucoamylase, OH OHC OH pb 15% Mwt 645.6 and sucrase inhibitor, HO OH ur 94% (iv) PSA 329 A˚ 2 antidiabetic HN HO O O OH log P −7.91 O HO O O OH H OH HO

1/ . ± . . ± . t 2 6 7 1 7d V 0 54 0 14 DIGITOXIN OH . ± . O F 95% CL 0 06 0 02 Na-K-ATPase membrane pump H O pb 97±0.5% Mwt 764.9 inhibitor, cardiac digitalis O OH O ur 32±15% PSA 183 A˚ 2 glycoside HO H log P 2.74 Active metabolite: digoxin O OH H O H OH O O H H

1/ t 2 38–42 h V 4–7 DIGOXIN OH O F 70–80% CL 1.8 Na-K-ATPase membrane pump H O pb 20–30% Mwt 780.9 inhibitor, cardiac digitalis O OH O ur 70–80% PSA 203 A˚ 2 glycoside for treatment of HO OH H log P 1.29 atrial ﬁbrillation O OH H O H OH O O H H

15 Phenols

Phenol has been used as antiseptic since 1867, when Joseph Lister, professor of surgery at the University of Glasgow, published his ﬁrst article on the use of phenol in ‘‘antiseptic surgery.’’ The antiseptic properties of phenol had, however, already been noticed by the discoverer of phenol (‘‘carbolic acid’’), Friedlieb Runge, in 1833. Today, phenol and low-molecular-weight phenols are important antiseptics used in numerous products, such as toothpaste, soap, and other detergents [1]. Other important drugs containing a phenol substructure are antipyretics (paracetamol), steroids, and analogs of catecholamines [2] (see also Table 15.1). The most common metabolic transformation of phenols is O-glucuronidation and O-sulfation. If the 2- or 4-position of a phenol is unsubstituted, aromatic hydroxylation may occur. Phenols with hydroxyl, alkoxy, or amino group in ortho or para position may be oxidized to quinones. The kinetics of these processes vary widely and are difﬁcult to estimate. Some examples of phenol metabolism are shown in Scheme 15.1.

hydroxylation glucuronidation hydroxylation OH glucuronidation OH sulfation H OH O H H N HO H Acetaminophen (paracetamol) Ethinyl estradiol Propofol − t1/2 2 h, F 88% t1/2 10 h, F 51% t1/2 0.5 1.0 h, F <5% CYP450

OH O O R-SH O

N R-SH: glutathione, N H SR proteins

Scheme 15.1 Metabolism of phenols. Some catechols (1,2-dihydroxybenzenes) can be methylated at high rates by catechol-O-methyltransferase (COMT). This is the reason for the short half-lives of dopamine, adrenaline, isoproterenol, and related catecholamines. By replacing the catechol substructure with 1,3-dihydroxybenzene, the plasma half-life of such

OH OH H O H HO N HO HO N N CN HO HO OH NO2 Isoproterenol Orciprenaline Entacapone − − − − t1/2 3 min, F 25% t1/2 2 6 h, F 10 40% t1/2 2 4 h, F 25 36%

Scheme 15.2 Dihydroxybenzenes as drugs.

Simultaneous dosing of a COMT inhibitor, such as entacapone, is another strategy to increase the half-life of catechols. The effect of levodopa (treatment for Parkinson’s disease) can be prolonged by the peripheral decarboxylase inhibitor carbidopa (Scheme 15.3). The latter suppresses the peripheral conversion of levodopa into dopamine, so that larger quantities of levodopa can reach the CNS, where decarboxylation to dopamine occurs. Both the absorption from the small bowel and the crossing of the blood–brain barrier (bbb) of levodopa are mediated by an active transport system for aromatic amino acids. Carbidopa does not cross the bbb.

HO CO2H HO CO2H

NH NH HO 2 HO H2N Levodopa Carbidopa − t1/2 1.4 h, F 41% t1/2 2.1 h, F 40 70%

Scheme 15.3

If a metabolically labile phenol is important for biological activity of a lead, the aromatic hydroxyl group may be replaced by a bioisostere. Phenol bioisosteres include benzpyrazoles, benzimidazoles, anilines, sulfonamides of anilines, and sometimes ﬂuorobenzenes. The half-life of the vasodilator bamethan can, for instance, be signiﬁcantly enhanced by replacing the phenolic hydroxyl group by a methanesulfonylamino group or an amino group (Scheme 15.4).

OH OH H OH H H N N Cl N O O S HO N H2N H Cl Bamethan Sotalol Clenbuterol − − t1/2 2.5 h, F 75% t1/2 12 h, F 90 100% t1/2 34 h, F 89 98%

Scheme 15.4 Bioisosteres of phenols. 84 15 Phenols

References

1. Sneader, W. (1995) Antiseptics I. Drug News Perspect., 8, 504–508. 2. Sneader, W. (1996) Antipyretic analgesics. Drug News Perspect., 9, 61–64. 3. Bird, T.G.C., Arnould, J.C., Bertrandie, A., and Jung, F.H. (1992) Pharmacokinetics of catechol cephalosporins. The effect of incorporating substituents into the catechol moiety on pharmacokinetics in a marmoset model. J. Med. Chem., 35, 2643–2651.

Table 15.1 Phenols and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 1–5 h V –PHENOL OH F 90% CL – Topical anesthetic and pb – Mwt 94.1 antiseptic ur 52% PSA 20.2 A˚ 2 Metabolism: log P 1.54 glucuronidation, sulfation

1/ t 2 0.5–1.0 h V 3–14 PROPOFOL F <5% CL 19–33 Anesthetic; Metabolism: OH pb 96–99% Mwt 178.3 aromatic hydroxylation ur <0.3% PSA 20.2 A˚ 2 (position 4), sulfation, log P 3.66 glucuronidation; Prodrug: fospropofol

1/ ∗ t 2 0.8–0.9 h V 0.33 FOSPROPOFOL ∗ O O OH F – CL 4.3–6.0 iv P pb 98% Mwt 288.3 Prodrug of propofol O OH ur <0.02%∗ PSA 85.8 A˚ 2 log P 2.70

1/ Cl t 2 27–35 h V 0.35 PENTACHLOROPHENOL ∗ ∗ Cl OH F 91% CL 0.02 rat pb >96% Mwt 266.3 Insecticide, herbicide 2 Cl Cl ur 74% PSA 20.2 A˚ Metabolism: Cl log P 5.12 glucuronidation

t1/ 2.0±0.4h V 0.95±0.12 ACETAMINOPHEN, PARACETAMOL OH 2 O F 88±15% CL 5.0±1.4 Analgesic, hepatotoxic pb Negligible Mwt 151.2 Metabolites: O-glucuronide, N H ur 3±1% PSA 49.3 A˚ 2 O-sulfate, quinoneimine, log P 0.48 conjugate with glutathione 85

1/ t 2 0.7–1.5 h V 1–2 PHENACETIN F Low CL ∗∗equal to hepatic blood ﬂow O O pb 33% Mwt 179.2 Analgesic; extensive ﬁrst pass ur 0.1% PSA 38.3 A˚ 2 metabolism (O-deethylation, N H log P 1.66 N-deacetylation, N-hydroxylation); withdrawn in 1983 because of hepatotoxicity

1/ ∗ t 2 3h V – DILOXANIDE FUROATE ∗ ∗ O F 60–90% CL – phenol on oral dosing of ester O O pb – Mwt 234.1 Amebicide; Metabolism: Cl O N ur – PSA 40.5 A˚ 2 ester hydrolysis, then H Cl log P 1.67 glucuronidation

1/ . ± . . ± . t 2 1 8 0 6h V 1 1 0 2 EDROPHONIUM . ± . N OH F Low CL 9 2 3 2 Cholinergic, antidote to curare pb Low Mwt 166.2 ur 65% PSA 20.2 A˚ 2 log P −2.07

1/ O t 2 36 h (iv) V 30 TEBUFELONE F 100% (rat) CL 9.9 Antiinﬂammatory, hepatotoxic pb – Mwt 300.4 2 OH ur – PSA 37.3 A˚ log P 5.8

1/ O t 2 100–112 h V – DARBUFELONE F 99% (rat) CL – Antiinﬂammatory N S pb – Mwt 332.5 OH ur <0.2% PSA 101 A˚ 2 H N 2 log P 4.74

1/ t 2 1.1–1.3 h V 0.12 TOLCAPONE O F 60–72% CL 1.7–1.9 COMT inhibitor, antiparkinsonian OH pb 99.8% Mwt 273.2 Metabolism: glucuronidation, ur 0.5% PSA 103 A˚ 2 O-methylation of 3-hydroxy, OH log P 4.15 reduction of nitro to amino, NO2 hydroxylation of methyl, oxidation of methyl to CO2H

1/ O t 2 4h V – NEBICAPONE OH F >55% (rat) CL – COMT inhibitor pb >99% Mwt 273.2 Metabolism: glucuronidation, OH ur <1% PSA 103 A˚ 2 O-methylation

NO2 log P 3.84

(continued overleaf ) 86 15 Phenols

1/ O t 2 2.4–3.5 h V 0.28 ENTACAPONE OH F 25–36% CL 12 COMT inhibitor; antiparkinsonian N pb 98% Mwt 305.3 Metabolism: E to Z isomerization, CN OH ur <0.5% PSA 130 A˚ 2 glucuronidation, hydrogenation, = NO2 log P 2.38 and cleavage of C C double bond

1/ O N t 2 7h V 0.9 (rat) NICLOSAMIDE 2 OH O F 10% (rat) CL 20 (rat, iv) Anthelmintic N pb – Mwt 327.1 Metabolism: glucuronidation H 2 Cl ur – PSA 95.2 A˚ log P 3.77 Cl

t1/ 22 h V – EZETIMIBE OH 2 F Unknown CL – Oral antilipemic; active O pb 99.7% Mwt 409.4 metabolite: phenol glucuronide N 2 F ur 2% PSA 60.8 A˚ Further metabolism: oxidation of log P 3.96 secondary alcohol to ketone F OH

1/ ± . ± . t 2 32 12 h V 8 9 4 2 DRONABINOL, THC F 8±4% CL 3.5±0.9 Antiemetic, appetite stimulant OH H pb 95% Mwt 314.5 Active metabolite: 11-hydroxy ur <1% PSA 29.5 A˚ 2 H log P 6.84 O

1/ O t 2 2h V 12.5 NABILONE F 20% CL 0.7 Antiemetic OH H pb – Mwt 372.5 Metabolism: reduction of ketone to ur 22% (iv) PSA 46.5 A˚ 2 alcohol, H log P 7.25 hydroxylation at CH2CH3 O

1/ ± α t 2 81 19 h V –D--TOCOPHEROL F 35–85% CL – Vitamin OH pb – Mwt 430.7 Prodrug: acetate ur <1% PSA 29.5 A˚ 2 O log P 11.0

t1/ <6h V – BISPHENOL A HO OH 2 F Low CL – Monomer for polycarbonates and pb – Mwt 228.3 epoxy resins, fungicide ur – PSA 40.5 A˚ 2 Metabolism: glucuronidation log P 3.64 87

1/ Cl Cl t 2 6–44 h V – HEXACHLOROPHENE Cl Cl F – CL – Antiseptic, disinfectant pb 92% Mwt 406.9 2 Cl Cl ur – PSA 40.5 A˚ OH OH log P 7.17

1/ t 2 1.2 h V – CLOFOCTOL, OCTOFENE F High CL – Antibiotic Cl pb – Mwt 365.3 Metabolism: glucuronidation ur – PSA 20.2 A˚ 2 log P 8.25 OH Cl

1/ ∗ O O t 2 18–29 h V – CYCLOFENIL F –CL– ∗diphenol on oral dosing of O O pb – Mwt 364.4 diacetate; gonad-stimulating ur 0% PSA 52.6 A˚ 2 principle; withdrawn because log P 4.66 of hepatotoxicity

1/ ∗ t 2 28 h V 5 DIETHYLSTILBESTROL ∗ OH F –CL– monkey; Estrogen; Metabolism: pb 50–95% Mwt 268.4 aromatic hydroxylation to catechol, ur – PSA 40.5 A˚ 2 hydroxylation of methyl groups; log P 5.33 withdrawn in 1975 as it causes HO adenocarcinoma of vagina in daughters after use in early pregnancy

1/ t 2 23–47 d V – PROBUCOL F 2–8% CL – Hypolipidemic; poor absorbtion pb – Mwt 516.8 (1–14%) because of poor solubility HO OH ur <2% PSA 91.1 A˚ 2 Metabolism: oxidative cyclization log P 9.00 to dispiroquinone (bond formation S S between the 4-positions of the phenols), then formation of sulfur-free diphenoquinone

1/ ± . ± . t 2 28 9h V 1 0 0 1 DAPSONE O O F 93±8% CL 0.60±0.17 Antibacterial (leprostatic) S pb 73±1% Mwt 248.3 Metabolism: N-hydroxylation, ur 15% PSA 94.6 A˚ 2 N-acetylation; causes H2N NH2 log P 0.99 methemoglobin formation and hemolysis

t1/ 3–8 h V – SULFOXONE O O 2 F – CL – Antibacterial (leprostatic) HO O S O OH S S pb 69% Mwt 404.5 Metabolism: hydrolysis to dapsone N N ur – PSA 180 A˚ 2 H H log P −1.91

(continued overleaf ) 88 15 Phenols

1/ ± ∗ t 2 14 2h V – BENZARONE F –CL– ∗after oral administration of pb >99% Mwt 266.3 benzbromarone O ur – PSA 50.4 A˚ 2 Capillary protectant log P 4.73 Metabolism: O-sulfation, O-glucuronidation, ethyl hydroxylation; O OH no unchanged benzarone can be detected in plasma after oral administration

1/ ± O t 2 3 1h V 19 BENZBROMARONE Br F – CL – Uricosuric, hepatotoxic pb >99% Mwt 424.1 Metabolism: debromination to 2 O OH ur 0% PSA 50.4 A˚ benzarone Br log P 6.65

1/ O t 2 10 h V – IPRIFLAVONE F 24% (rat) CL – Treatment of osteoporosis pb – Mwt 280.3 Metabolism: phenyl ˚ 2 O O ur PSA 35.5 A 4-hydroxylation, log P 4.25 O-deisopropylation

1/ OH t 2 8h V 3–5 DAIDZEIN O F 2–10%∗ CL 7.7 ∗rat pb – Mwt 254.2 Natural isoﬂavone, phytoestrogen ur 30–50% PSA 66.8 A˚ 2 Metabolism: glucuronidation, HO O log P 2.63 sulfation

1/ OH t 2 10 h V 2.5 GENISTEIN OH O F 20–40%∗ CL – ∗rat pb – Mwt 270.2 Natural isoﬂavone: phytoestrogen ur 9% PSA 87.0 A˚ 2 Metabolism: glucuronidation, HO O log P 3.11 sulfation

1/ OH O t 2 0.6 h (iv) V 0.1 QUERCETIN OH F <1% CL 11 Capillary protectant pb 99% Mwt 302.2 OH 2 HO O ur 0.5% PSA 127 A˚ log P 1.99 OH

1/ O t 2 5min V – FLAVOXATE F 100% CL – ∗acid pb 99.5%∗ Mwt 391.5 Antispasmodic: does not cross bbb N 2 O ur 0% PSA 55.8 A˚ Metabolism: hydrolysis of ester log P 4.27 O O 89

1/ OH t 2 0.7 h (iv) V – IDRONOXIL F 1% CL – Proapoptotic agent: oncolytic pb – Mwt 240.3 ur 0% PSA 49.7 A˚ 2 HO O log P 3.35

1/ t 2 short V –CURCUMIN O OH F 0% CL – Natural dye and antioxidant MeO OMe pb – Mwt 368.4 Metabolism: glucuronidation, ur 0% PSA 93.1 A˚ 2 sulfation, hydrogenation of C=C HO OH log P 3.07 double bonds, reduction of ketone to alcohol

1/ O OH t 2 12 h V – ALIZARIN OH F – CL Biological stain pb – Mwt 240.2 Metabolism: O-glucuronidation ur 18–36% PSA 74.6 A˚ 2 O log P 2.91

1/ ∗ O t 2 4–8 h V – DIACEREIN, DIACETYLRHEIN ∗ ∗ CO2H F 35% CL – rhein on oral dosing of diacerein pb 99%∗ Mwt 368.3 Antiarthritic ur 20%∗ PSA 124 A˚ 2 Metabolism: deacetylation to rhein, O O O log P 3.13 then glucuronidation, sulfation

O O

1/ ± . ± . OH t 2 8 4h V 0 36 0 15 ETOPOSIDE ± . ± . O OH F 52 17% CL 0 68 0 23 Antineoplastic pb 96±0.4% Mwt 588.6 O 2 O O ur 35±5% PSA 161 A˚ O log P 0.28 O O O

MeO OMe OH

(continued overleaf ) 90 15 Phenols

1/ ± . ± . OH t 2 9 3h V 0 22 0 05 TENIPOSIDE F 20–71% CL 0.37±0.13 Antineoplastic S O OH pb 99% Mwt 656.7 Metabolism: O-demethylation O ± ˚ 2 O O ur 8 2% PSA 189 A log P 1.56 O O O O

MeO OMe OH

1/ OH t 2 2–12 h V 0.3 NK-611 O N F 100% CL 0.4 Antineoplastic pb 99% Mwt 615.6 Metabolites: N-desmethyl, cis-lactone O 2 O O ur 3–26% (iv) PSA 143.9 A˚ O log P 1.14 O O O

MeO OMe OH

1/ OH O OH t 2 25–27 h V 0.25 HYPERICIN F – CL 0.13 Antidepressant, phototoxic pb – Mwt 504.4 component of St. John’s wort HO ur – PSA 156 A˚ 2 Metabolism: negligible HO log P 10.8

OH O OH

1/ OH O OH t 2 16–36 h V 0.56 PSEUDOHYPERICIN F – CL 0.62 Dye from Hypericum perforatum pb – Mwt 520.4 (St. John’s wort) OH 2 HO ur – PSA 176 A˚ HO log P 9.29

OH O OH

16 Ethers

Dialkyl ethers are more soluble in water than alkanes and can, therefore, be used to improve the solubility and prevent ﬁrst-pass metabolism of hydrophobic leads. The replacement of a CH2 group by oxygen leads to compounds with diverging boiling and melting points, which indicates that oxygen is not a good bioisostere of the methylene group. Such modiﬁcation may in fact lead to compounds with quite different properties (Scheme 16.1).

O O O bp 49 °C 67 °C 98 °C 91 °C 159 °C 170 °C mp −94 °C −108 °C −91 °C −122 °C −100 °C −30 °C log P 2.64 0.47 4.27 2.06 3.74 2.68

Scheme 16.1

If a lead contains a phenol substructure and shows poor absorption or extensive ﬁrst-pass metabolism, etheriﬁcation may enhance oral bioavailability. Because alkoxyarenes are often rapidly dealkylated in vivo, some ethers may serve as prodrug of alcohols or phenols. Thus, codeine or hydrocodone are more orally bioavailable than their corresponding phenolic metabolites morphine and hydromorphone (Scheme 16.2). For phenacetin, metabolic deethylation is so fast that it can hardly be detected in plasma, and its apparent oral availability is, therefore, low. Because the main metabolite of phenacetin, acetaminophen, has good oral availability, the latter can be used as analgetic as well. In fact, phenacetin is more damaging to the kidneys and liver than acetaminophen and is, therefore, no longer available in many countries. Ethoxybenzenes should be considered as metabolically questionable and, if possible, avoided.

O OH HO MeO

in vivo O O N N NH H H H H NH O O O O Hydromorphone Hydrocodone Phenacetin Acetaminophen t 1/2 2.4 h t1/2 5 h t1/2 1 h t1/2 2 h F 24% F 65% F low F 88%

Scheme 16.2 Effect of phenol O-alkylation on PK.

16.1 Metabolism

Alkyl ethers with at least one hydrogen atom in α-position may be α-hydroxylated via hydride abstraction. The resulting hemiacetal can fragment into an alcohol and an aldehyde or a ketone. With the exception of some methoxy- or ethoxyarenes, most ethers are metabolized rather slowly, and numerous long-acting drugs contain ether substructures (Table 16.1). Ethers of 2-alkoxyethanols (e.g., poly(ethylene glycol) [1]) or 2-aminoethanols are more stable than simple alkyl ethers, as a comparison of some of the metabolites of clemastine and doxylamine shows (Scheme 16.3). The main metabolite of clemastine is the tertiary alcohol resulting from oxidative ether cleavage; no such cleavage occurs in doxylamine.

Cl Cl Cl

O N OH + O N

Clemastine main metabolite OH t 1/2 22 h, F 37%

CO2H O O CO H O N 2 + N

N N N

Doxylamine t 1/2 9 h, F 25%

Scheme 16.3 Metabolism of clemastine and doxylamine. Reference 93

If a lead contains an unstable alkyl ether, its cleavage may be prevented by conversion into a cyclopropylmethylether. One instance of this strategy is the long-acting β-blocker betaxolol (Scheme 16.4).

OH OH H H O N O N

O O

Metoprolol Betaxolol − t1/2 3 h, F 38% t1/2 14 22 h, F 89%

Scheme 16.4 Stabilization of methyl ethers by cyclopropylation. The conversion of methyl groups into cyclopropylmethyl groups does, however, not always lead to drugs with better pharmacokinetics (PK). The lipophilic benzodiazepines ﬂutoprazepam and prazepam, for instance, are quickly N- dealkylated in vivo and have shorter half-lives than their methyl analogs ﬂudiazepam and diazepam (Scheme 16.5).

O O O O N N N N

Cl N Cl N Cl N Cl N

F F

Fludiazepam Flutoprazepam Diazepam Prazepam t 1.3 h t 1/2 36 h t1/2 < 6 h; F 85% t1/2 43 h; F 100% 1/2

Scheme 16.5 Effect of cyclopropylation in benzodiazepines.

Reference

1. Harris, J.M. and Chess, R.B. (2003) Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov., 2, 214–221.

Table 16.1 Ethers, acetals, and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ . ± . . ± . O NO t 2 1 0 0 5h V 3 9 1 5 ISOSORBIDE DINITRATE H 2 ± ± O F 22 14% CL 45 20 Vasodilator pb 28±12% Mwt 236.1 O ur <1% PSA 129 A˚ 2 H O2N O log P 0.95

(continued overleaf ) 94 16 Ethers

1/ ± . ± . t 2 5 1h V 0 8 0 3 ISOSORBIDE MONONITRATE H O NO2 O F 93±13% CL 6±2 Vasodilator pb 0–5% Mwt 191.1 O ur <5% PSA 93.7 A˚ 2 HO H log P −0.18

1/ OH t 2 5–10 h V – ISOSORBIDE H > O F 80% CL – Osmotic agent, treatment of pb – Mwt 146.1 hydrocephalus O ur High PSA 58.9 A˚ 2 HO H log P −1.19

1/ ± t 2 8 3h V 1.7 PARALDEHYDE F – CL 2.2 Sedative, hypnotic O O pb – Mwt 132.2 ur Negligible PSA 27.7 A˚ 2 O log P 1.02

1/ t 2 27 h V – METALDEHYDE O F –CL–∗dog O pb – Mwt 176.2 Molluscicide, crosses bbb O ur 1–8%∗ PSA 36.9 A˚ 2 O log P 1.36

1/ ∗ . ∗ CO2H t 2 2.6 h V 9 5 ARTELINIC ACID F 80%∗ CL 15∗∗dog O O O pb – Mwt 418.5 Antimalarial ∗ O ur 0% PSA 83.5 A˚ 2 Metabolism: O-debenzylation H H log P 4.89 O H

1/ t 2 2–3 h V 1–10 ARTEMETHER F 43% CL/F 3.7 Antimalarial O O O pb 95% Mwt 298.4 Metabolism: O-demethylation O ur – PSA 46.2 A˚ 2 H H log P 3.07 OMe H

1/ t 2 0.2–0.7 h V 15 ARTESUNATE O O F 30% (rat) CL 1070 Antimalarial O pb 75% Mwt 384.4 O O ˚ 2 H H ur – PSA 101 A OH O log P 2.94 H O 95

1/ . ± . / ± t 2 2 6 0 6h V F 16 9 ARTEMISININ F Low CL/F 66±49 Natural antimalarial O O O pb 77% Mwt 282.3 O ur <1% PSA 54.0 A˚ 2 H H log P 2.27 O H

1/ H t 2 3.2 h (iv) V 2.5 BILOBALIDE O O O F – CL 10 Neuroprotectant O pb – Mwt 326.3 O ˚ 2 O OH ur 30% PSA 119 A H OH log P 4.46

NH 1/ O 2 t 2 20–24 h V 0.55–0.83 TOPIRAMATE O O S O F 80–95% CL – Anticonvulsant, antimigraine O O O pb 10–20% Mwt 339.4 Metabolism: acetal hydrolysis, ˚ 2 O ur 35–80% PSA 124 A hydroxylation of CH3 log P 2.16

17 Epoxides

Epoxides are strong alkylating reagents, but when stabilized by stereochemical or electronic effects, their toxicity may be sufﬁciently low to be suitable as nonalkylating drugs. Tropane-derived epoxides, for instance, are metabolically stable and only react with nucleophiles under forcing conditions. Stable epoxides can, therefore, be considered as PK-modifying group (e.g., to enhance solubility and metabolic stability) or as a possibility to get around others patents. Examples of nonalkylating epoxides are shown in Scheme 17.1.

O H N S O H N O O O O HO HO S Scopolamine Tiotropium t1/2 3 h, F 27% t1/2 5 d, F 2–3%

O O S O OH O H N HN H O CO2Me O OH O Eplerenone Ixabepilone t1/2 4–6 h t1/2 17–52 h (iv)

Scheme 17.1 Epoxide-containing drugs.

18 Peroxides

Despite being strong oxidants and thermally unstable, organic peroxides are occasionally used as drugs. These include the artemisinin-derived antimalarials (Table 16.1) and the anthelmintic ascaridole (Scheme 18.1). One of the metabolic transformations of these compounds includes reductive O–O bond cleavage.

O O O O H O H O O O O O OH O H H Artenimol Artemotil Ascaridole t 1/2 1.6 h, F 19% (rat) F 35% (rat)

Scheme 18.1 Peroxide-containing drugs.

19 Thiols

Because sulfur is less electronegative than oxygen, the S−H bond is weaker and less strongly polarized than the O−H bond. Owing to the weaker hydrogen bonding ability, thiols have lower boiling point and are more lipophilic but more acidic than the corresponding alcohols (Scheme 19.1).

OH SH OH SH

bp 117 °C 98 °C 82 °C 64 °C mp −90 °C −116 °C 26 °C 1 °C pKa (in H2O) 16 10.7 18 11.1 log P 0.84 2.46 0.58 2.21

Scheme 19.1 Physicochemical properties of alcohols and thiols.

Free sulfhydryl groups are air sensitive and highly nucleophilic and will only be used as structural element of a drug if indispensable. Thiol-containing drugs include enzyme inhibitors such as captopril or omapatrilate (binding of SH to Zn2+ of angiotensin-converting enzyme (ACE)), mucolytics such as N-acetylcysteine (as a reducing agent for disulﬁde bonds in proteins; also as an antidote for glutathione- depleting poisons), antidotes for heavy metal poisoning such as dimercaprol, and organ-protecting adjuvants for chemotherapy such as MESNA (Scheme 19.2). Some gold complexes, used for the treatment of rheumatoid arthritis, contain thiol-based ligands.

CO2H O O HS N N HS N S NH HS ONa N N O CO2H H O Captopril N-Acetylcysteine Mercaptopurine MESNA t1/2 2.2 h t1/2 2 h t1/2 0.9 h t1/2 0.4–8 h F 65% F 10% F 12% F 45–79%

H S H N Ph SH CO2H N CO2H SH N HS HS N NH NH2 O O CO2H Methimazole O Omapatrilate Penicillamine Tiopronin t 3–6 h 1/2 t 14–19 h t 1.5–3.0 h t 19–54 h F 95% 1/2 1/2 1/2 F 30% F 40–70% F 63%

Scheme 19.2 Thiols as drugs.

Typical metabolic transformations of thiols include oxidative disulﬁde formation, desulfuration, and S-methylation. 100

20 Thioethers

The thioether group is a structural element of many drugs and does usually not lead to any toxic metabolites. Thioethers have higher boiling points and higher melting points but are less water soluble than the corresponding ethers (Scheme 20.1). Thus, while THF and water are miscible, tetrahydrothiophene and water form two phases.

O O S O S

bp −25 °C 37 °C 49 °C 81 °C 119 °C 67 °C 88 °C 121 °C mp −139 °C −98 °C −94 °C 7 °C −12 °C −108 °C −45 °C −96 °C log P 0.02 0.98 2.64 3.16 3.69 0.47 1.00 1.61

Scheme 20.1 Comparison of alkanes, ethers, and thioethers.

If a thioether-containing lead shows poor oral bioavailability or short half-life because of S-oxidation, the thioether may be replaced by the similarly sized, bioisosteric ethylene group (CH2CH2) or oxymethylene group (OCH2). Such modiﬁcation was realized in phenothiazine-based antipsychotics, which often are poorly orally available. The corresponding dibenzazepines show, however, similar pharmacokinetics (PK) as the phenothiazines, probably because metabolic transformations other than S-oxidation proceed faster (N-dealkylation, N-oxidation, or aromatic hydroxylation). The compounds shown in Scheme 20.2, for instance, have similar plasma half-lives and oral bioavailabilities, no matter if they contain thioethers or not.

N N

S Promazine Imipramine t1/2 8 h t1/212 h F 17% F 39%

N N N N

S S O Chlorprothixene Amitriptyline Dothiepin Doxepin t1/2 10 h t1/2 22 h t1/2 19 h t1/2 17 h F 44% F 55% F 30% F 27%

Scheme 20.2 The effect of thioethers on the PK-properties of drugs.

Sulfur is more electronegative than carbon and may be introduced into a lead to lower its basicity. A famous example of this strategy is cimetidine, a histamine H2 antagonist for gastric acid suppression [1]. The H2 antagonist burimamide was potent but showed little oral bioavailability (Scheme 20.3). Replacement of a methylene group by sulfur reduced the basicity of the imidazole fragment, and with an additional methyl group, a more lipophilic, orally available drug (metiamide) was obtained. Unfortunately, the thiocarbonyl group caused hepatotoxicity, which was ﬁnally overcome by replacement of the thiourea by a cyanoguanidine.

H H H H H H N N N N N N N N S N S S S N N N N CN H H H Burimamide Metiamide Cimetidine low oral bioavailability high oral bioavailability t1/2 2 h, F 84% high hepatotoxicity

Scheme 20.3 Cimetidine and its leads.

20.1 Metabolism

Typical metabolic transformations of thioethers include dealkylation (same mechanism as dealkylation of ethers or amines) and oxidation to sulfoxides and sulfones. The oxidation to sulfoxides is reversible, and sulfoxides, for example, sulindac or DMSO, can undergo metabolic reduction to thioethers. 102 20 Thioethers

The most important metabolic pathway of sulfoxides is, however, their oxidation to sulfones. The rapid oxidation of thioethers in the liver can lead to low oral bioavailability. Specially sensitive are highly lipophilic thioethers (e.g., phenothiazines) and sterically unshielded thioethers (e.g., arene-bound SCH3). Occasionally, thioethers have been introduced into drugs to shorten their half-life, for instance, in the barbiturate methitural. If a drug is hydrophilic, however, sulfoxide formation may be acceptably slow. Some examples of thioethers with relatively long half-lives and good oral availabilities are shown in Scheme 20.4.

CO2H Cl O H H H H H N O SMe N O N N N N S N S H H2N S O N HO OH NO2 O OH Ranitidine CO2H Ceftibuten Clindamycin t1/2 2 h F 52% t1/2 2.5 h t1/2 2.9 h F 100% F 87%

S F CO2H S O O O O EtO2C S S H2N NH N N N Ph N S Ph N S H CO H Cl N O 2 Temocapril Benzthiazide Rufloxacin t 10 h t1/2 10–22 h (diacid) 1/2 t1/2 38 h F 52% F 65% F 70%

Scheme 20.4 Thioethers as drugs.

Metabolic S-oxidation can on occasions generate electrophilic intermediates that can cause toxicity or an immune response by protein alkylation. The withdrawn diuretic ticrynafen (tienilic acid), for instance, is converted in the liver into a highly reactive thiophene S-oxide, which induces an autoimmune response toward a liver protein (Scheme 20.5). Although any 2-unsubstituted thiophene may undergo these reactions, the required dose of drug is also a critical parameter for adverse drug reactions, and numerous safe, thiophene-containing drugs have been developed. Reference 103

O CO2H O CO2H CYP2C9

S Cl S Cl O Cl O O Cl Ticrynafen Ticrynafen S-oxide protein-XH t1/2 6 h H2O

O CO2H O CO2H HO protein-X S Cl S Cl O Cl O Cl 5-Hydroxyticrynafen Alkylated, immunogenic protein (antigen)

Scheme 20.5 Metabolism of ticrynafen.

Reference

1. Durant, G.J., Emmett, J.C., Ganellin, C.R., Miles, P.D., Parsons, M.E., Prain, H.D., and White, G.R. (1977) Cyanoguanidine–thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. J. Med. Chem., 20, 901–906. 104

21 Sulfoxides

Despite its chemical reactivity, numerous drugs contain a sulfoxide group. In the case of proton pump inhibitors, sulfoxide reactivity is essential to their mechanism of action (Scheme 21.1). Omeprazole, for instance, has a short half-life under acidic conditions (2 min at pH 1–3) and covalently binds to H+,K+-ATPase to form a nonfunctional complex with a half-life of about 24 h. The enzyme is reactivated by glutathione-mediated reductive cleavage of the S−S bond.

OMe OMe OMe S O N OH H acid N S N N N S NNH N OMe NH OH MeO Omeprazole MeO t1/2 0.7 h, F 53% OMe OMe

S enzyme N N S enzyme-SH S NN NNH

MeO MeO

Scheme 21.1 Mechanism of action of omeprazole.

Other sulfoxides with higher metabolic stability than the proton pump inhibitors include the nonsteroidal antiinﬂammatory drug (NSAID) sulindac and the alcohol metabolite of the immunosuppressant oxisuran (Scheme 21.2).

O O OH O CO H 2 N S in vivo N S S O Sulindac F Oxisuran Alcohol metabolite t1/2 15 h, F 90% t1/2 1 h t1/2 55 h

Scheme 21.2 Sulfoxides as drugs.

Besides undergoing Pummerer-type reactions as electrophiles, sulfoxides are mainly oxidized in vivo to sulfones or reduced to thioethers. 106

22 Sulfones

Sulfones are chemically and metabolically stable, highly polar functional groups, and have often been used for lead optimization. This group can be used to enhance solubility and reduce the rate of metabolic transformations or as bioisostere of a sulfonamide or an amide. Examples of sulfone-containing drugs are shown in Scheme 22.1.

O O O NH2 O O O O O O2N S S N S N NH N N 2 H

S H2N OMe N O O EMD 87580 Amisulpride Tinidazole − − t1/2 3 7 h, F > 90% t1/2 12 h, F 50% t1/2 12 14 h, F 95% O O S O O S Cl N O

N Cl N Etoricoxib Chlormezanone − t1/2 21 27 h, F 100% t1/2 41 h

Scheme 22.1 Sulfones as drugs.

23 Aliphatic Amines

Aliphatic amines are basic compounds (pKa 8–10) and will be protonated to a large extent in most organs. As salts, aliphatic amines dissolve more readily in water than free (unprotonated) amines, and drugs containing an amine functionality are, therefore, often formulated as ammonium salts. Further advantages of salts include a higher melting point, lower vapor pressure (no smell), higher stability toward oxidants, light, or carbon dioxide, and an overall better processability. Natural compounds with an amine functionality, present in our food or body, include amino acids, hormones (serotonin, dopamine), or decarboxylated amino acids such as histamine, tyramine, or tryptamine. A huge number of drugs contain the amine substructure; these include enzyme inhibitors and agonists or antagonists of natural neurotransmitters, in which the amino group is a key pharmacophore (e.g. Table 23.1). Amino groups may, however, also be introduced into drugs to modify their physicochemical and pharmacokinetic properties. The solubility of highly insoluble, neutral organic compounds may, for instance, be enhanced by linking them to a basic functional group (see, e.g., camptothecin and topotecan, Chapter 60). Moreover, because biological membranes consist of negatively charged phospholipids, basic drugs tend to be distributed more extensively in tissue than neutral or acidic drugs of similar log P and molecular weight. This leads to higher volumes of distribution and, all other factors being constant, to a longer half-life of basic drugs if compared to a similar neutral or acidic drug. Therefore, the half-life of a drug may be enhanced with basic functional groups. Successful examples of this strategy are given in Scheme 23.1.

N Cl O N Cl Cl

iPrO2C CO2Me MeO2C CO2Et MeO2C CO2Et O N N N NH2 H H H Isradipine Felodipine Amlodipine t1/2 8 h, F 19% t1/2 14 h, F 15% t1/2 39 h, F 74% V 4 l kg–1 V 10 l kg–1 V 16 l kg–1

O N

HO OH HO OH OH OH OH OH O O N O O N

OOO OOO

O Erythromycin O Azithromycin OMe t1/2 1.6 h, F 35% OMe t1/2 40 h, F 37% V 0.8 l kg–1 V 31 l kg–1 OH OH

MeO O N O O O N Codeine N Pholcodine H H H H t1/2 3 h, F 50% t1/2 37 h, F high HO V 2.6 l kg–1 HO V 36−49 l kg–1

O Ph N N O H2N Disopyramide t 6 h, F 83% N 1/2 H2N N V 0.59 l kg–1 Cl Disobutamide t1/2 54 h

Dantrolene N N t 9 h, F 70% H 1/2 O N O N V 0.54 l kg–1 O O N N N O2N Cl N Azimilide O O − t1/2 4 5 d, F 85% V 26 l kg–1

Scheme 23.1 Effect of amines on PK. 23 Aliphatic Amines 109

Not always does the half-life of a drug increase when introducing an amine functionality. The volume of distribution also depends on the affinity of a drug to plasma proteins. If a modified drug binds stronger to plasma proteins, its volume of distribution and plasma half-life may be lowered if compared to a less protein-bound drug. Drugs containing two amino groups close to each other (1,2-diaminoethanes, piperazines) are not completely diprotonated in human plasma. The formation of a dication requires a low pH (ethylenediamine: pKa 10.7, 7.6; piperazine: pKa 9.8, 5.6), and drugs with these substructures are mainly monoprotonated in plasma and most tissues. Thus, replacement of the dimethylamino group in chlorpromazine by a substituted piperazine does not significantly enhance the volume of distribution (Scheme 23.2).

OH N N N N N

N Cl N Cl N Cl

S S S Chlorpromazine Prochlorperazine Perphenazine − − t1/2 30 h, F 32% t1/2 7 h, F 13 20% t1/2 10 h, F 20 40% V 21 l kg–1 V 22−24 l kg–1 V 12−24 l kg–1

Scheme 23.2 Comparison of monoamines with piperazines.

As illustrated by the examples above, dimethylamino groups can often be replaced by other amine-containing groups, without signiﬁcant alteration of biological properties. A large number of alternatives for a dimethylamino group have been used with success to ﬁne-tune potency, selectivity, and PK properties. Some of the many possibilities are shown in Scheme 23.3.

H N N NH N N R R R 2 R R

H N R N N N N R R R R

H O N N O N R N N R NH R R R

Scheme 23.3 Typical basic substituents used in drugs. 110 23 Aliphatic Amines

23.1 Basicity

Because only uncharged xenobiotics can cross cell membranes without the aid of a carrier mechanism, the basicity of amines can have an impact on their PK properties. Unfortunately, in many leads, the amino group is a critical pharmacophore and cannot be replaced by an uncharged group without losing afﬁnity to the target protein. It may be possible, however, to slightly lower the basicity of an amine and attain a signiﬁcant improvement of absorption from the gastrointestinal (GI) tract and blood–brain barrier (bbb) penetration. The structure of an alkyl substituent may modify the basicity of an amine. Alternatively, a heteroatom or an electron-withdrawing substituent will often decrease the pKa of an amine. Illustrative examples are given in Scheme 23.4.

NH2 NH2 NH2 NH2 NH2 NH NH2 2 pK a 10.2 9.72 9.1010.7 10.2 9.49 7.87 (in water)

O F NH NH 2 2 NC NH2 H2N HO NH NH NH2 EtO 2 F 2 9.34 9.98 9.50 7.75 7.52 5.34

O CN N N N CN N N N H N N H H H H 10.65 7.65 4.55 10.98 11.22 8.36 11.29 7.98

Scheme 23.4 Basicity of amines.

Amines with cyano, sulfonyl, or nitro groups in α-orβ-position are not stable and can undergo hydrolysis or β-elimination. The rate of such reactions may, however, be sufﬁciently low to allow their use in lead optimization.

23.2 Metabolism

Amines are readily oxidized, and typical hepatic transformations include N- dealkylation and N-oxidation. Amines with tert-alkyl substituents can be dealkylated by decarboxylation of an intermediate amino acid [1] (Scheme 23.5). 23.2 Metabolism 111

R R R CYP450 Hydrolysis R N or N N R R NH R R O O OH

R CYP450 R R R OH N N N N R R OH R O R O

R R R N N OH R R NH R O

Scheme 23.5 Metabolic N-dealkylation of amines.

The rate of metabolic degradation, which ultimately determines the extent of ﬁrst- pass effect and thus the oral bioavailability and half-life, strongly depends on the overall structure of the drug and cannot be readily predicted. Important factors include the lipophilicity and polar surface area (PSA) of the whole molecule and the basicity of the amino group and its steric accessibility. It is often observed that primary and secondary amines are dealkylated more slowly than similar tertiary amines. A selection of amines with long plasma half-lives is given in Scheme 23.6.

N O NH2 O N Cl HN N CF3 Cl NH

Quinupramine Neramexane Tesofensine O t 29−33 h t 35−40 h t 8 d CF3 1/2 1/2 1/2 Rolapitant F 75% F 90% F 90% t1/2 8 d

HO O HO O N N H N N N N N N O N N CF3 NH2 CF3 Linagliptin Lasofoxifene Mefloquine t 5 d t 6 d 1/2 1/2 t1/2 20 d F (rat) 15−51% F 60%

Scheme 23.6 Long-lived amine-containing drugs. 112 23 Aliphatic Amines

23.3 Rates of N-Dealkylation

The dimethylamino and methylamino groups are present in numerous drugs. Their half-life varies strongly, but in many instances, the half-life increases on demethylation. Thus, secondary methylamines are metabolically more stable than the corresponding tertiary dimethylamines. In addition to the examples shown in Scheme 23.7, this effect has been observed for zimeldine, ruboxistaurine, sertraline, tilidine, and amiodarone (N-deethylation).

H N in vivo N in vivo NH2

Cl Cl Cl

Sibutramine Desmethylsibutramine Didesmethylsibutramine t1/2 1 h t1/2 14 h t1/2 16 h

H O N N N

N in vivo N N +

Imipramine Desipramine Imipramine N-oxide t1/2 12 h t1/2 22 h t1/2 1.8 h (iv) F 39% F 38%

N N H H N N N NH

O in vivo O

HN N N Imatinib HN N N N-Desmethyl- − t1/2 18 22 h imatinib F 98% N N t1/2 40 h

H O N O NH2 in vivo

F3C F3C

Fluoxetine Desmethylfluoxetine t1/2 53 h, F 70% t1/2 6.5 d

O N O NH in vivo Cl Cl

Cl Cl Tesofensine Desmethyltesofensine t 8 d, 1/2 t1/2 14 d F 90%

Scheme 23.7 Metabolic N-dealkylation of amines. 23.3 Rates of N-Dealkylation 113

F F O O H N N N in vivo N H H HN HN N O N O H Sunitinib H Desethylsunitinib − − t1/2 40 60 h t1/2 80 110 h F 70%

H N N HN HN in vivo Chloroquine Desethyl- t1/2 41 d chloroquine Cl N Cl N F 89% t1/2 15 d

F C F C 3 OH 3 OH in vivo N NH

Halofantrine − Cl Cl t1/2 6 10 d Cl Cl F 6% (dog) Desbutylhalofantrine − t1/2 3 11 d

HN NH2 Rasagiline in vivo t1/2 1.3 h F 36%

O NH O N in vivo N N Lorcainide Desisopropyl- lorcainide t1/2 7.6 h F 1−65% t1/2 27 h Cl Cl

Scheme 23.7 (Continued).

Prodrugs are launched occasionally in which the parent drug is formed by metabolic N-dealkylation of an amine. Three such examples are shown in Scheme 23.8. The aim with such prodrugs is to keep the compound inactive during its absorption from the GI tract to avoid unwanted side effects or to enhance its lipophilicity to improve oral bioavailability. 114 23 Aliphatic Amines

O N NH in vivo N N Cl

Lofepramine Desipramine t1/2 5 h, F 10% t1/2 22 h, F 38% Cl Cl N NH in vivo N N N

Rupatadine Desloratadine t1/2 6 h, F 50% t1/2 18 h, F high O O

F CO2H F CO2H in vivo O N N N N O S S O N HN Prulifloxacin Ulifloxacin − not detectable in plasma t1/2 10 12 h after oral dosing

Scheme 23.8 Metabolic N-dealkylation of amine prodrugs.

Highly insoluble primary or secondary amines may be acylated with glycine or short peptides (see also Chapter 33). This can result in a prodrug of higher solubility, which will usually be rapidly deacylated in human plasma.

Reference

1. Kamm, J.J. and Szuna, A. (1973) Studies on an unusual N-dealkylation reaction. II. Characteristics of the enzyme system and a proposed pathway for the reaction. J. Pharmacol. Exp. Ther., 184, 729–738. 115

Table 23.1 Aliphatic amines. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ ± / ± t 2 30 14 h V F 25 14 RIMANTADINE F 99% (dog) CL/F 10±6 Antiviral NH2 pb 40% Mwt 179.3 Metabolism: hydroxylation ur 9±4% PSA 26.0 A˚ 2 of adamantane log P 3.31

1/ ± . . ± . t 2 16 3 4h V 6 6 1 5 AMANTADINE NH2 F 70±20% CL 4.8±0.8 Antiviral, antiparkinsonian pb 67% Mwt 151.3 No metabolism ur 70±20% PSA 26 A˚ 2 log P 2.44

t1/ 60–100 h V 10 MEMANTINE NH 2 2 F 100% CL – Muscle relaxant, treatment of pb 45% Mwt 179.3 Alzheimer’s disease ur 48% PSA 26.0 A˚ 2 Metabolites: 4- and 6-hydroxy, log P 3.00 dimethylnitrosoadamantane

1/ t 2 35–40 h V 11 NERAMEXANE F 90% CL – NMDA antagonist NH2 pb – Mwt 169.3 Metabolism: oxidation of 2 ur 30–40% PSA 26.0 A˚ CH3 to CO2H log P 4.00

1/ t 2 3–5 h V 2–3 CYCLOHEXYLAMINE NH2 F – CL – Metabolite of cyclamate (see below) pb – Mwt 99.2 Metabolites: cyclohexanol, ur – PSA 26.0 A˚ 2 trans-1,2-dihydroxycyclohexane log P 1.50

1/ ∗ t 2 8h V – CYCLAMATE H < ∗ N OH F 37% CL – rat, dog S pb – Mwt 179.2 Artiﬁcial sweetener O O ur 30–40% PSA 74.8 A˚ 2 Metabolite: cyclohexylamine log P 1.03

t1/ 12–14 h V 7.0–7.3 PRAMIPEXOLE H 2 S N F 90% CL 0.11 Antiparkinsonian pb – Mwt 211.3 H2N N ur 90% PSA 79.2 A˚ 2 log P 1.42

1/ t 2 5.6 h V – THAM H2N F – CL – For treatment of metabolic H2N pb – Mwt 121.1 acidosis H N ˚ 2 2 OH ur 82% PSA 86.7 A log P −2.52 (continued overleaf ) 116 23 Aliphatic Amines

1/ t 2 0.6 h V 0.13 ETHYLENEDIAMINE F 34% CL – Hydrochloride as urinary NH2 pb – Mwt 60.1 acidiﬁer H2N ur 3% PSA 52.0 A˚ 2 log P −2.06

1/ . ± . . ± . t 2 3 1 0 4h V 1 6 0 2 ETHAMBUTOL H F 77±8% CL 8.6±0.8 Antibacterial N OH < HO N pb 5% Mwt 204.3 Metabolism: oxidation of H ur 79±3% PSA 64.5 A˚ 2 hydroxymethylene to carboxyl log P −0.29

1/ > t 2 17–36 h V 30 TERBINAFINE F 40% CL – Topical antifungal pb >99% Mwt 291.4 Metabolism: N-demethylation, N ur Negligible PSA 3.24 A˚ 2 hydroxylation of tert-butyl, log P 5.58 oxidation of tert-butyl to carboxyisopropyl, N-de(naphthyl)methylation to naphthaldehyde and naphthoic acid

1/ ∗ t 2 35–150 h V – BUTENAFINE F –CL–∗after topical administration N pb – Mwt 317.5 Topical antifungal ur – PSA 3.24 A˚ 2 Metabolism: hydroxylation log P 6.00 of tert-butyl

1/ t 2 7–51 h V 6.2 PHENCYCLIDINE F 50–90% CL 5.4 Anesthetic, hallucinogenic pb 60–70% Mwt 243.4 Metabolism: piperidine N ur 9–10% PSA 3.24 A˚ 2 4-hydroxylation, cyclohexane log P 4.25 hydroxylation, piperidine ring opening by N-dealkylation

t1/ 6–12 h V 5.5–7.0 BROMHEXINE NH2 2 Br F 25% CL – Expectorant, mucolytic N pb 99% Mwt 376.1 Metabolite: ambroxol (see below) ur 0.1% PSA 29.3 A˚ 2 log P 4.80 Br 117

1/ OH t 2 7–12 h V 1.5 AMBROXOL NH2 F 70–80% CL 8.7 Expectorant, active N-desmethyl Br pb 90% Mwt 378.1 metabolite of bromhexine N H ur 5–6% PSA 58.3 A˚ 2 Metabolite: dibromoanthranilic log P 4.57 acid Br

1/ ∗ t 2 7–10 min V – PROCARBAZINE ∗ H F 100% CL – iv N pb – Mwt 221.3 Antineoplastic; crosses bbb; N H H ur <5% PSA 53.2 A˚ 2 highly carcinogenic N log P 0.06 Metabolite: terephthalic O N-isopropyl monoamide

t1/ 21–24 h V 2.3 SAFINAMIDE F 2 F 80–92% CL – MAO inhibitor pb 92% Mwt 302.3 Metabolism: N-dealkylation, N CONH2 ur 7–10% PSA 64.3 A˚ 2 hydrolysis of amide, SO H O O 3 log P 2.20 then glucuronidation

t1/ 8.9±1.8h V 5.9±0.8BRETYLIUM Br 2 F 23±9% CL 10±2 Antiadrenergic, antiarrhythmic N pb 0–8% Mwt 243.2 ur 77±15% PSA 0.0 A˚ 2 log P −0.90

1/ O t 2 1.5 h V – PINAVERIUM Br F <0.5% CL – Antispasmodic N pb 95–98% Mwt 511.5 Metabolism: O-demethylation, ur – PSA 36.9 A˚ 2 hydroxylation at pinanyl, MeO O log P 1.25 N-debenzylation, then oxidative OMe degradation of morpholine

MAO, monoamine oxidase; NMDA, N-methyl-D-aspartic acid; t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area. 118

24 Quaternary Ammonium Salts

Drugs containing quaternary ammonium groups are mainly designed to interact with the various acetylcholine receptors and with the enzyme acetylcholinesterase. These include muscarinic receptor agonists and antagonists (e.g., quaternized belladonna alkaloids as bronchodilators and antispasmodics), nicotinic receptor agonists and antagonists (neuromuscular blocking agents, ganglionic blocking agents), ganglionic stimulants, and antiacetylcholinesterase agents (cholinergics) [1]. In all these drugs, the quaternary ammonium group is the key pharmacophore. Further, quaternary ammonium salts include the antiarrhythmic bretylium, the opiate antagonist methylnaltrexone, and topical disinfectants, such as benzalkonium (Scheme 24.1).

O Acetylcholinesterase N N O HO Acetylcholine Choline

O N O N O N N O N OH O HO Butylscopolammonium Neostigmine Pralidoxime t 1/2 5 h, F < 1% t 1/2 1.3 h, F 1–2% t 1/2 2–3 h, F 20–30% muscarinic receptor antagonist anticholinesterase agent cholinesterase reactivator O O Br N H N N C H N N N n (2n+1) H H O H Bretylium Benzalkonium O Pipecuronium t 1/2 9 h, F 23% (n = 8, 10, 12, 14, 16, 18) t 1/2 2.5 h antiarrhythmic disinfectant neuromuscular blocking agent

Scheme 24.1 Quaternary ammonium salts as drugs.

A common feature of most quaternary ammonium salts is their low oral bioavailability. Because the small intestine behaves essentially as a large, lipophilic membrane, charged molecules cannot be readily absorbed. For this reason, an animal killed by parenteral administration of tubocurarine (a quaternary ammonium salt) can be safely eaten because of the low oral bioavailability of the poison. Small, charged molecules may nevertheless be absorbed either by means of an active transport mechanism or via small hydrophilic pores. The latter have diameters of 3–8 A˚ and will enable the passage of either extended, long molecules − − of up to 400 g mol 1 or more spherical molecules of up to 200 g mol 1. The quaternization of an amino-group-containing drug will usually yield a compound with lower ability to cross the blood–brain barrier (bbb) and lower oral bioavailability. The in vitro afﬁnity to the target protein may, however, be similar to that of the tertiary amine. Because of the low oral bioavailability of salts, quaternization is not a common strategy to block central effects of a drug. Examples include the antispasmodic emepronium (Table 46.1) and methylnaltrexone (Table 52.1), a parenteral opiate antagonist designed to prevent some of the side effects of opioids, such as constipation. The metabolic stability of quaternary ammonium salts depends on the type of substituents, but usually, no metabolic degradation of this functional group is seen in vivo. For instance, only 0.06% of a dose of methylnaltrexone is demethylated in vivo to naltrexone. Molecules containing two basic sites (amines or ammonium salts) separated by around 14 A˚ (∼8–12 bonds) may act as neuromuscular blocking agents. Such compounds (e.g., tubocurarine, pipecuronium, atracurium, decamethonium, etc.) interrupt nervous signal transmission and are used as adjuvant muscle relaxants during surgery. High doses of such compounds will, however, cause death by asphyxiation. Before testing diamines in animals, these compounds should, therefore, also be checked for neuromuscular blocking activity.

Reference

1. (a) Sneader, W. (1996) Curare. Drug News Perspect., 9, 627–630; (b) Sneader, W. (1997) Synthetic muscle relaxants. Drug News Perspect., 10, 113–117. 120

25 Amidines

Amidines (pKa 12) are almost as basic as guanidines and often show poor oral bioavailability and little ability to cross membranes. One exception is low- molecular-weight amidines and imidazolines, which can be highly orally available (Scheme 25.1). Nevertheless, many amidine-containing drugs have to be inhaled or dosed parenterally. These include α-adrenergic agonists and antagonists, antiprotozoals, and antithrombotics (Table 26.1). The benzamidine substructure of the latter is a mimetic of arginine of the natural substrate of the proteases involved in the blood clotting cascade. This amidine is difﬁcult to replace by other functional groups without losing biological activity.

OH H N H Cl N N H N N N O N Cl

Cifenline Lofexidine Phentolamine t 1/2 7–11 h t 1/2 11 h t 1/2 5–7 h F 85–100% F > 90% F low O O OMe NH NH N O NH HN H2N NH2 O O H2N O O NH Roxifiban Pentamidine t 1/2 5 d (acid) t 1/2 3 d F 21% (acid on F negligible administration of ester)

Scheme 25.1 Amidines as drugs.

Because of their poor oral bioavailability, various prodrugs of amidines have been developed (Scheme 25.2). These include N-hydroxyamidines, which undergo quick

O O O OEt O O O H N N N N N OEt H H H H N O N HO HO NH NH Sibrafiban Ximelagatran t 1/2 9–12 h; F 36% t 1/2 3–5 h; F 20% (amidine/acid on oral (amidine/acid on oral administration of the prodrug) administration of the prodrug)

O N H N N O N H O N N OEt

O NH Dabigatran etexilate t 1/2 12–14 h; F 7% (amidine/acid on oral administration of the prodrug)

Scheme 25.2 Prodrugs of amidines.

Reference

1. Reeh, C., Wundt, J., and Clement, B. (2007) N,N -Dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines. J. Med. Chem., 50, 6730–6734. 122

26 Guanidines, Acylguanidines, and Biguanides

Guanidines are strong bases (pKa 13) and will be protonated and positively charged in most tissues. Guanidines are highly water soluble, but have poor oral bioavailabilities and cannot efﬁciently cross membranes or the blood–brain barrier (bbb) (Scheme 26.1). In most guanidine-containing drugs, the guanidine is the key pharmacophore and difﬁcult to replace by other, less basic functional groups. Examples include histamine H2 antagonists (antiulceratives, e.g., famotidine, ebrotidine), ganglionic blocking agents (antihypertensives, e.g., guanethidine), neuraminidase inhibitors (antivirals, e.g., zanamivir, peramivir), antibacterials (streptomycin), and 5-HT4 agonist tegaserod (treatment of constipation).

HN NH O O H NH2 2 HN N HN N S N O S N NH2 HN NH HN H NH S 2 NH OH Famotidine Guanethidine t 3−4 h t 2−5 d HO C O OH 1/2 1/2 2 H F 40−45% F 3−50% OH Zanamivir − NH t 1/2 3 5 h O 2 OMe F 2% O OH HO N NH2 Cl O O O OH NH H H N NH2 N N N N H HO NH HO N NH HN NH2 H 2 NH Cl OH OH Streptomycin Tegaserod Guanabenz − t 1/2 2.6 h t 1/2 11 h t 1/2 4 14 h F < 1% F 11% F unknown

Scheme 26.1 Guanidines as drugs. Several 2-(arylamino)imidazolines have been developed, mainly as α-adrenergic agonists (Scheme 26.2, Table 26.1). These are slightly less basic and have higher oral bioavailabilities than purely aliphatic guanidines. Some of these compounds can be used as topical, intraocular pressure lowering agents for the treatment of glaucoma [1].

Cl Cl H H OMe H H N N H H N N N N N N N N N Cl Cl N S N Clonidine Tizanidine Moxonidine − − t 1/2 12 h t 1/2 2 4 h t 1/2 2 3 h F 75−95% F 21−40% F 88%

Scheme 26.2 N-arylguanidines as drugs.

26.1 Acylguanidines

Acylated guanidines (pKa 8–9) are less basic than alkyl- or arylguanidines or aliphatic amines and are readily absorbed from the gastrointestinal (GI) tract. Some, for example, guanfacine (Scheme 26.3), even cross the bbb, despite their large polar surface area (PSA). Most of these compounds are sodium channel blockers and are being used as diuretics, antihypertensives, or cardioprotectants.

O NH Cl O NH O O O NH Cl S N N NH2 N NH2 H N NH H H 2 S Cl H N N NH 2 2 O O Guanfacine Amiloride EMD 87580 − − t 1/2 14 23 h t 1/2 21 h t 1/2 3 7 h F 60−100% F 50% F > 90%

Scheme 26.3 Acylguanidines as drugs.

26.2 Biguanides

Substituted biguanides are being used as antidiabetics, antiprotozoals, and disinfectants (Scheme 26.4). The antidiabetic effect of biguanides is caused by insulin sensitization of peripheral tissue and by inhibition of hepatic gluconeogenesis. Only biguanides of low molecular weight (<200 g mol−1) are orally bioavailable; larger molecules require either parenteral or topical administration or will, on oral administration, only be active in the GI tract. 124 26 Guanidines, Acylguanidines, and Biguanides

H H H H H H N N NH2 N N NH2 Cl N N N

NH NH NH NH NH NH Cl

Metformin Phenformin Chlorproguanil − − t 1/2 2 19 h t 1/2 5 15 h t 1/2 18 h F 40−60% antidiabetic antimalarial antidiabetic Cl NH NH H H H N N N N N N H H H NH NH Cl Chlorhexidine disinfectant

Scheme 26.4 Biguanides as drugs.

Reference

1. Sugrue, M.F. (1997) New approaches to antiglaucoma therapy. J. Med. Chem., 40, 2793–2809.

Table 26.1 Amidines, guanidines, and related compounds. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 3–10 h V 1.6 TOLAZOLINE H F 90–100% CL – α-Adrenergic antagonist, treatment N pb – Mwt 160.2 of pulmonary hypertension in 2 N ur – PSA 24.4 A˚ newborns log P 1.80

1/ ∗ t 2 35 h V –OXYMETAZOLINE H ∗ N OH F –CL–intranasal pb – Mwt 260.4 α-Adrenergic agonist, N 2 ur – PSA 44.6 A˚ nasal decongestant; too toxic for log P 3.76 other than topical administration

1/ t 2 – V –OXANTEL N F 8–10% CL – Anthelmintic against gut parasites OH N pb – Mwt 216.3 2 ur – PSA 35.8 A˚ log P 1.87

1/ t 2 – V – PYRANTEL N F Low CL – Anthelmintic against gut parasites N S pb – Mwt 206.3 2 ur <7% PSA 43.8 A˚ log P 2.08 125

1/ t 2 5–7 h V – PHENTOLAMINE H F Low CL – α-Adrenergic antagonist, N N pb 54% Mwt 281.4 antihypertensive 2 N ur 3–10% PSA 47.9 A˚ Metabolism: log P 4.08 oxidation of CH3 to CO2H OH

1/ t 2 7–11 h V 4–7 CIFENLINE, CIBENZOLINE F 85–100% CL 9–15 Antiarrhythmic H N pb 50–60% Mwt 262.4 Metabolism: 4-hydroxylation of 2 ur 50–60% PSA 24.4 A˚ phenyl, dehydrogenation of N log P 3.49 imidazolidine

t1/ 8–9 h V 4–5 RILMENIDINE H 2 F 100% CL 6.6 α -Adrenergic agonist, O N 2 pb <10% Mwt 180.3 antihypertensive, little 2 N ur 64% PSA 33.6 A˚ metabolism log P 1.48

1/ Cl t 2 12–24 h V – MAZINDOL F 93% CL – CNS stimulant, anorexic pb – Mwt 284.7 Metabolism: oxidation of . ˚ 2 HO N ur – PSA 35 8 A imidazolidine to imidazolidinone log P 2.36 N

1/ t 2 32 h V –CICLAZINDOL F High CL – Antidepressant; Metabolism: Cl pb – Mwt 298.8 hydrolysis of amidine to HO . ˚ 2 N ur 20% PSA 35 8 A N-(3-aminopropyl)indolone, N log P 1.18 oxidative N-dealkylation to 3-aminopropionic acids

1/ H t 2 2–6 h V – ETIFOXINE, ETAFENOXINE N N F 90% CL – Anxiolytic pb – Mwt 300.8 Metabolism: N-deethylation, O 2 Cl ur – PSA 33.6 A˚ phenyl 4-hydroxylation log P 4.23

1/ O t 2 4.2 h (iv) V 3.3 IDAZOXAN F 1–23%∗ CL 10 ∗rat H α N pb – Mwt 204.2 2-Adrenergic antagonist O 2 ur – PSA 42.9 A˚ Metabolism (rat): aromatic N log P 2.31 hydroxylation (continued overleaf ) 126 26 Guanidines, Acylguanidines, and Biguanides

1/ Cl t 2 11 h V – LOFEXIDINE F >90% CL – Antihypertensive H N pb 80–90% Mwt 259.1 Main metabolite: 2,6-dichlorophenol O 2 ur 5–20% PSA 33.6 A˚ N Cl log P 3.04

1/ t 2 3–4 h V 2.9 ALINIDINE Cl F 100% CL 10 Antihypertensive H pb – Mwt 270.2 N N 2 ur 79–90% PSA 27.6 A˚ N log P 3.49 Cl

1/ ± . ± . Cl t 2 12 7h V 2 1 0 4 CLONIDINE H H F 75–95% CL 3.1±1.2 α -Adrenergic agonist, N N 2 pb 20–30% Mwt 230.1 antihypertensive, analgesic, crosses N ± . ˚ 2 Cl ur 62 11% PSA 36 4 A bbb; Metabolism: aromatic log P 2.36 4-hydroxylation

1/ Cl t 2 8h V – APRACLONIDINE H H F –CL–α -Adrenergic agonist to reduce N N 2 pb – Mwt 245.1 postoperative intraocular pressure 2 N ur – PSA 62.4 A˚ (topical application) Cl NH2 log P 1.68

1/ Cl t 2 2.1–4.2 h V 2.4 TIZANIDINE H H F 21–40% CL 11 α2-Adrenergic agonist, muscle N N pb 30% Mwt 253.7 relaxant 2 N ur <3% PSA 90.4 A˚ Metabolism: oxidation N log P 2.39 of imidazoline, N-dealkylation S N

1/ H H t 2 5–7 h V – INDANAZOLINE N N F –CL–α-Adrenergic agonist, pb 32% Mwt 201.3 vasoconstrictor, nasal decongestant N 2 ur – PSA 36.4 A˚ log P 2.26

1/ Br t 2 3h V – BRIMONIDINE H H F –CL–α -Adrenergic agonist, N N 2 N pb – Mwt 292.1 antiglaucoma; Metabolism: 2 N ur – PSA 62.2 A˚ dehydrogenation of imidazolidine, N log P 1.20 further oxidation to imidazolones 127

1/ OMe t 2 1.5–2.5 h V 1.8–3.0 MOXONIDINE H H F 88% CL 11–15 Antihypertensive N N N pb 6–8% Mwt 241.7 Metabolism: hydroxylation at CH3 2 N ur 46–70% PSA 71.4 A˚ and imidazolidine Cl N log P 0.33

1/ t 2 3–5 h V – TIAMENIDINE H H N N F – CL – Antihypertensive pb – Mwt 215.7 N . ˚ 2 Cl S ur – PSA 64 7 A log P 1.87

1/ ∗ t 2 4–6 h V 3–4 LEVAMISOLE > ∗∗ S N F 70% CL 39–49 rabbit pb 51% Mwt 204.3 Anthelmintic N 2 ur 2–5% PSA 40.9 A˚ Metabolite: 4-hydroxyphenyl log P 1.84

1/ ± NH NH t 2 3d V 190 70 PENTAMIDINE F Negligible CL 18±7 Antiprotozoal NH H2N 2 pb 69% Mwt 340.4 Metabolism (rat): N-hydroxylation, 2 O O ur 2–18% PSA 118 A˚ hydroxylation of alkylene chain, log P 2.85 O-dealkylation

1/ N NH2 t 2 23 min V – NAFAMOSTAT F Low CL – Serine protease inhibitor, O NH2 pb – Mwt 347.4 anticoagulant H2N O 2 ur – PSA 138 A˚ Metabolism: ester hydrolysis NH log P 2.06

1/ t 2 7–12 h V – GUANIDINE HN NH2 F – CL – Antiviral, antifungal, antipyretic pb – Mwt 59.1 NH 2 2 ur – PSA 75.9 A˚ log P −1.25

1/ t 2 6–8 wk V – CREATINE F –CL3.3 HN N CO2H pb – Mwt 131.1 2 NH2 ur – PSA 90.4 A˚ log P −1.26

t1/ 4h V – CREATININE HN 2 N F –CL3.3 HN pb – Mwt 113.1 2 ur – PSA 58.7 A˚ O log P −0.80 (continued overleaf ) 128 26 Guanidines, Acylguanidines, and Biguanides

t1/ 10–18 h V – PEMOLINE HN 2 O F – CL – CNS stimulant; withdrawn in 2005 HN pb 30–50% Mwt 176.2 because of hepatotoxicity 2 ur 50% PSA 64.7 A˚ O log P 0.43

1/ t 2 4h V – AMINOGUANIDINE N NH F – CL – Nitric oxide synthase inhibitor, H N 2 2 pb – Mwt 74.1 antidiabetic NH 2 2 ur – PSA 87.9 A˚ log P −1.48

1/ t 2 4–9 h V 2.8 BETHANIDINE H F – CL – Antihypertensive; Metabolism (rat, N N pb – Mwt 177.3 dog): N-demethylation, 2 ur High PSA 36.4 A˚ N-debenzylation, N-hydroxylation; NH log P 1.73 no signiﬁcant metabolism in man

1/ OMe t 2 9–20 h V –MEOBENTINE H F – CL – Antiarrhythmic N N pb – Mwt 207.3 Metabolism: N- and . ˚ 2 NH ur – PSA 45 7 A O-demethylation log P 1.62

1/ t 2 16–30 h V – DEBRISOQUIN F – CL – Antihypertensive; Metabolism: HN N pb – Mwt 175.2 benzylic 4-hydroxylation, then 2 ur – PSA 53.1 A˚ elimination of water, aromatic NH2 log P 0.75 hydroxylation, glucuronidation

1/ O t 2 – V – GUANOXAN H F >50% CL – Antihypertensive HN N pb – Mwt 207.2 Metabolism: aromatic 6- and O 2 ur 1–60% PSA 80.4 A˚ 7-hydroxylation NH2 log P 0.84

1/ t 2 10–12 h V 10 GUANADREL O F 85% CL 41 Antihypertensive, does not H pb 20% Mwt 213.3 cross bbb HN N 2 O ur 40–50% PSA 80.4 A˚ Metabolism: hydrolysis log P 0.55 of acetal NH2

1/ H t 2 2–5 d V – GUANETHIDINE HN N F 3–50% CL – Antihypertensive N pb 0% Mwt 198.3 Metabolism: oxidation to N-oxide NH 2 2 ur 25–50% PSA 65.1 A˚ log P 1.10 129

1/ t 2 1.3 h V 0.3 L-ARGININE CO2H H F 68±9% CL 15±4 Insulin secretagogue HN N NH2 pb – Mwt 174.2 ˚ 2 NH2 ur – PSA 125 A log P −1.65

t1/ 1.2–2.3 h V 0.6–0.8 L-N-METHYLARGININE CO H 2 H 2 F – CL 8.0–9.5 Endogenous nitric oxide synthase N N NH pb Negligible Mwt 188.2 inhibitor 2 2 ur <1% PSA 111 A˚ Metabolism: hydrolysis of NH2 log P −0.08 guanidine to urea (citrulline)

1/ O t 2 8–21 h (iv) V 0.5 PERAMIVIR F Low CL 0.9–1.6 Neuraminidase inhibitor, antiviral HN pb <30% Mwt 328.4 H 2 H ur 90% PSA 149 A˚ N OH − . H2N log P 1 37 NH CO2H

1/ O OH t 2 2.6–5.1 h V 0.3 ZANAMIVIR ∗ ∗ OH F 2% CL 0.6–2.8 inhalation: 10–20% NH < H pb 10% Mwt 332.3 Neuraminidase inhibitor, antiviral 2 H2N N ˚ OH ur 80% PSA 198 A H log P −4.13 NH O

CO2H

1/ O OH t 2 3d V – LANINAMIVIR OH F – CL – Methylated zanamivir, antiviral NH H pb – Mwt 346.3 (inﬂuenza) 2 H2N N ˚ OMe ur – PSA 187 A H log P –3.06 NH O

CO2H

t1/ 2.6±0.4h V 0.25±0.02 STREPTOMYCIN NH2 2 H N NH2 2 OH F –CL1.2±0.3 Antibacterial O pb 48±14% Mwt 581.6 N N NH2 O 2 ur 55±5% PSA 331 A˚ HO O OH log P −1.22 O OH H N O HO OH OH

(continued overleaf ) 130 26 Guanidines, Acylguanidines, and Biguanides

1/ ± t 2 11 5h V 5.2 TEGASEROD OMe F 11% CL 18.3 5-HT4 agonist, treatment of pb 98% Mwt 301.4 constipation 2 ur – PSA 85.3 A˚ Metabolism: hydrolysis of NH 2 log P 2.91 hydrazone, oxidation to HN N N N indole-3-carboxylic acid; withdrawn H in 2007 because of stroke and heart attack risk

1/ Cl t 2 4–14 h V 4–17 GUANABENZ NH α H 2 F – CL 100–180 2-Adrenergic agonist, N pb 90% Mwt 231.1 antihypertensive; Metabolites: 4- N NH2 2 ur <1% PSA 74.3 A˚ hydroxy, 2,6-dichlorobenzylalcohol, Cl log P 2.66 2,6-dichlorobenzaldehyde

t1/ 14–23 h V 3.9–6.5 GUANFACINE Cl 2 O NH2 F 60–100% CL 2.6–5.2 α2-Adrenergic agonist, pb 64% Mwt 246.1 antihypertensive; Metabolism: N NH 2 2 ur 24–37% PSA 79.0 A˚ aromatic 3-hydroxylation, then Cl log P 1.33 glucuronidation, sulfation

1/ t 2 3.5 h (iv) V – CARIPORIDE O O O NH2 F – CL – Cardioprotective, sodium/proton S N NH2 pb – Mwt 283.4 exchange inhibitor (NHE-1) 2 ur – PSA 121 A˚ log P −1.01

1/ ∗ t 2 2.2 h V 1.1–1.5 ENIPORIDE O O O NH2 F –CL8.2∗iv S N NH2 pb 72% Mwt 320.4 Cardioprotective, sodium/proton 2 ur 43%∗ PSA 126 A˚ exchange inhibitor (NHE-1) N log P −1.03 Metabolism: hydrolysis of pyrrole to 4-aminobenzamide

1/ O O O NH2 t 2 3–7 h V 0.8–2.1 EMD 87580 > S F 90% CL 2.3–5.7 Cardioprotective, sodium/proton N NH2 pb 27% Mwt 333.4 exchange inhibitor (NHE-1) ˚ 2 S ur 90% PSA 164 A log P −1.66 O O

1/ ± ± t 2 21 3h V 17 4AMILORIDE O NH2 F 50% CL 10±2 Sodium channel blocker, diuretic Cl N N NH2 pb 40% Mwt 229.6 2 ur 49±10% PSA 157 A˚ H N N NH 2 2 log P 0.93 131

1/ ∗ ∗ t 2 1.5 h V 3.2 ZONIPORIDE O F –CL31∗∗iv, monkey N NH2 pb 77% Mwt 320.4 Cardioprotective, sodium/proton N NH 2 N 2 ur – PSA 105 A˚ exchange inhibitor (NHE-1) N log P 0.20 Metabolism: oxidation to 2-quinolone by aldehyde oxidase

1/ H t 2 1.3 h V 12 ANAGRELIDE N N F 70% CL 2.1 Antithrombocythemic; Metabolism: O pb – Mwt 256.1 hydroxylation of CH2CO, then N 2 Cl ur <1% PSA 44.7 A˚ hydrolysis to 2-amino-3,4- Cl log P 1.13 dihydro-5,6-dichloroquinazoline, then N-glucuronidation

1/ O t 2 10–17 h V 1 MUZOLIMINE F – CL – Diuretic N pb 65% Mwt 272.1 Metabolism: hydrolysis of amide, N 2 Cl ur 5% PSA 58.7 A˚ then decarboxylation Cl NH2 log P 2.10

1/ t 2 2–19 h V 0.9–3.9 METFORMIN NH NH 2 2 F 40–60% CL 6.3–10.1 Antidiabetic N N NH pb Negligible Mwt 129.2 No metabolites known 2 ur 100% PSA 89 A˚ log P −1.25

1/ t 2 2–6 h V 3 BUFORMIN NH2 NH2 F – CL – Antidiabetic, withdrawn in 1978 in N N NH pb 10% Mwt 157.2 most countries for risk of inducing 2 H ur 35% PSA 97.8 A˚ lactic acidosis log P −1.20

1/ t 2 5–15 h V 5–10 PHENFORMIN NH2 NH2 F 50–60% CL – Antidiabetic; Metabolism: pb 12–20% Mwt 205.3 aromatic 4-hydroxylation; N N NH 2 H ur 54% PSA 102.8 A˚ withdrawn in 1978 for risk of log P 0.1 inducing lactic acidosis

t1/ 12–15 h V 20–79 CHLORGUANIDE, PROGUANIL Cl 2 NH2 NH2 F >90% CL 14–27 Antimalarial pb 75% Mwt 253.7 Metabolism: cyclization to triazine N N N 2 H ur 40–60% PSA 83.8 A˚ log P 2.49

t1/ 18±7h V 29 CHLORPROGUANIL Cl 2 NH2 NH2 F –CL21±2 Antimalarial pb 63% Mwt 288.2 Metabolism: cyclization to triazine Cl N N N 2 H ur – PSA 83.8 A˚ log P 3.27 (continued overleaf ) 132 26 Guanidines, Acylguanidines, and Biguanides

1/ Cl t 2 – V – CHLORHEXIDINE NH2 NH2 F <1% CL – Antiseptic pb 87% Mwt 505.5 Metabolite: 4-chloroaniline N N N 2 H ur – PSA 168 A˚ H log P 4.58 N N N

NH NH Cl 2 2

1/ . ± . . ± . t 2 2 6 1 0h V 1 3 0 2 FAMOTIDINE NH H2N O O F 45±14% CL 7.1±1.7 Histamine H2 antagonist, H N S 2 N S N NH ± HN 2 pb 17 7% Mwt 337.5 antiulcerative 2 S ur 67±15% PSA 233 A˚ log P −1.66

1/ t 2 14–20 h V 1.7–2.7 EBROTIDINE Br NH H F – CL – Histamine H2 antagonist, H N N N 2 N S S pb – Mwt 477.4 antiulcerative HN O O 2 S ur 1% PSA 195 A˚ log P 2.83

1/ . ± . . ± . t 2 1 3 0 3h V 1 2 0 5 NIZATIDINE H H F 90% CL 10±3 Histamine H antagonist, N N N N 2 S pb 28±7% Mwt 331.5 antiulcerative; active metabolite: 2 S ur 61±3% PSA 140 A˚ N-monodesmethyl (t1/ 3.8±1.9h) NO2 2 log P −0.49

t1/ 2.1±0.2h V 1.3±0.4 RANITIDINE H H 2 ± . ± . N N N F 52 11% CL 10 4 1 1 Histamine H2 antagonist, O S pb 15±3% Mwt 314.4 antiulcerative 2 NO2 ur 69±6% PSA 112 A˚ Metabolites: N-oxide, S-oxide, log P −0.07 desmethyl

27 Anilines

Although a few unacylated aromatic amines have become successful drugs, medicinal chemists wisely tend to avoid this substructure because of its potential toxicity. Aniline itself is not carcinogenic, but it usually contains small amounts of highly carcinogenic impurities. Aniline is oxidized in vivo to N-phenylhydroxylamine and nitrosobenzene, which mediate the oxidation of hemoglobin (Fe2+) to methemoglobin (Fe3+) and lead to hemolytic anemia. Several drugs containing primary aromatic amines, such as nomifensine and phenacetin, had to be withdrawn because of kidney or liver toxicity. Some anilines are potent carcinogens, for instance, those shown in Scheme 27.1.

NH NH2 NH2 2 NH2 OMe

H2N H2N o-Toluidine 2,4-Diaminoanisol 4-Aminobiphenyl Benzidine

N N O NH2 NH N N

2-Naphthylamine Acetamidofluorene 4-Dimethylaminostilbene 4-Dimethylaminoazobenzene

Scheme 27.1 Carcinogenic anilines.

The carcinogenicity of anilines results from metabolic activation. The metabolites of electron-rich anilines include N-arylhydroxylamines, their O-sulfates, and nitrosoarenes, which are electrophilic arylating reagents capable of N-arylating nucleic acids. Compounds that may be metabolized to aromatic amines, such as N-arylamides, -ureas or -carbamates, nitroarenes, azo compounds, or aromatic azides, may also be carcinogenic.

Less electron-rich anilines do not readily undergo oxidative metabolism and are therefore less toxic. Derivatives of aminobenzoic acids and aminobenzenesulfonic acids are usually not carcinogenic, and many drugs with these substructures are currently in use. A selection of such ‘‘safe’’ aromatic amines is given in Scheme 27.2. These amines are weak bases (pKa 1.5–3.5) and will be unprotonated in most organs.

R R O OR N O N S O N H N X H N X 2 2 Y

Y = O, S, -(CH2)n-

Examples O O O O NH S N O N N H H N NH H2N 2 2 Procainamide Dapsone Eltoprazine t 1/2 3 h t 1/2 28 h t 1/2 7–9 h F 83% F 93% F 100%

H O N OMe N Cl O O N N N S N H N OMe H N H 2 O OMe H2N Prucalopride Sulfadoxine Desipramine t 1/2 22–34 h t 1/2 100–230 h t 1/2 22 h F > 90% F high F 38%

Scheme 27.2 Anilines of low toxicity.

If a lead contains a potentially toxic aromatic amine, it may be replaced by a heteroaromatic amine, such as an aminopyridine, aminopyrimidine, or aminothiazole. These heteroarenes are often metabolically stable and easier to prepare than substituted benzenes. Sterically undemanding aminopyridines may, however, be cytochrome P450 (CYP) inhibitors by virtue of their ability to bind to Fe2+/3+. Moreover, some polycyclic heteroaromatic amines are proven carcinogens (Chapter 59). 27.1 Metabolism 135

27.1 Metabolism

The typical metabolic transformations of anilines include N-dealkylation, N-oxidation, N-hydroxylation, aromatic hydroxylation, and reversible N-acetylation. The resulting N-arylhydroxylamines or N-nitrosoarenes are soft electrophiles and electrophilic arylating or aminating agents, in particular if these metabolites are further activated by O-sulfation or O-acetylation (Scheme 27.3). N-Acylanilines often undergo hydrolysis in vivo to release the unacylated aniline.

O N N

N N

OH O H N N N

OH O

NH2 NH N

+ NuH − H2O

H NH N NH2

O Nu H Nu

Scheme 27.3 Metabolic transformations of anilines. 136 27 Anilines

The rate and extent to which these chemical transformations occur are highly dependent on the precise structure of the aniline. Electron-poor anilines usually only undergo N-acetylation or no metabolic transformation at all. The examples in Scheme 27.4 illustrate the types of anilines that have acceptably low toxicities for humans (excluding nomifensine) and their plasma half-lives.

F CO2H H O N NH O H N 2 N N OEt N F H N NH2 Retigabine NH2 Afloqualone Mefenamic acid t 7–12 h t 3 h Nomifensine t 3 h 1/2 1/2 1/2 F 60% F low t 1/2 4 h F <30%

OH N O Br N OH N NH2 H NH O Br O N O H H NH2 O Ambroxol Aminogluthetimide Bepridil Ulipristal t 1/2 7–12 h t 1/2 13 h t 1/2 12 h t 1/2 32 h F 70–80% F >95% F 60% F 56% (acetate)

N NH 2 O H MeO N N N N H H NH O N NH2 MeO 2 OMe Trimetrexate O Entinostat t 1/2 12–20 h t 1/2 52 h F 44% F 85%

Scheme 27.4 Anilines as drugs. 137

28 Hydrazines, Acylhydrazines, and Hydrazones

The few alkylhydrazines used as drugs are monoamine oxidase (MAO) inhibitors (phenelzine and iproniazide), cytotoxic agents (procarbazine), antihypertensives (hydralazine), or amino acid decarboxylase inhibitors (carbidopa and benserazide) (Scheme 28.1). Alkylhydrazines (pKa 6.5–8.0) are less basic but more nucleophilic than amines, and acylhydrazines (pKa 2–3) or hydrazones (pKa 3–5) are still less basic than hydrazines.

O H H N HO N NH2 N NH2 H H N CO2H N HO H Phenelzine Procarbazine Carbidopa − − t1/2 1.2 h t1/2 7 10 min (iv), F 100% t1/2 2.1 h, F 40 70% O O OH H O NH N H N 2 N N H H HO N OH N N H NH2 OH Isoniazid Iproniazid Benserazide − t1/2 1 3 h t1/2 10 h F 70%

O O O H H S N N N NH2 O N NH H2N N 2 H N N Cl N N Clopamide Hydralazine Endralazine − − − − t1/2 8 12 h, F 85% t1/2 1 h, F 10 40% t1/2 2 5 h, F 74 99%

Scheme 28.1 Hydrazine derivatives as drugs.

Typical metabolic transformations of hydrazines include oxidation to azo and azoxy compounds, reductive N−N bond cleavage, and N-acetylation. If acylhydrazines are oxidized to azo compounds, these will usually quickly decompose by either nucleophilic displacement (hydrolysis) or homolytic C−N bond cleavage to yield highly reactive acyl radicals.

29 Aldehydes

Because aldehydes are highly electrophilic, few drugs contain a free aldehyde functionality. If they do, the formyl group will usually react quickly in vivo with some nucleophile, will be oxidized to an acid, or reduced to an alcohol. Thus, the sedative chloral hydrate is only a prodrug of trichloroethanol. Tucaresol is an electron-rich benzaldehyde of moderate electrophilicity, which acts by forming an imine (a Schiff base) with an amino group of hemoglobin and thereby increases the stability of the oxy-conformation of this protein. Cyclic acetals or hemiacetals of aldehydes are, however, sufﬁciently stable and a common substructure of many drugs, for example, in nucleoside or carbohydrate analogs (Scheme 29.1). Oximes (e.g., pralidoxime) and hydrazones (e.g., azimilide) of aldehydes can be found among therapeutic agents as well.

OH O Cl O OH Cl O Cl O N N N Chloral hydrate O N N O t1/2 short; rapid metabolization to − trichloroethanol (t1/2 4 12 h) Medifoxamine Doxofylline and trichloroacetic acid (t1/2 4 d) t1/2 2 h, F 21% t1/2 7 h, F 63%

H O O N NH O N NH2 N 2 OH HO O N HO O N Cl N F O Ph S Troxacitabine Temazepam Emtricitabine − − t1/2 11 h, F low t1/2 11 h, F 91% t1/2 7 18 h, F 75 93%

O CO2H O O O HO O S H2N N N H Tucaresol Metolazone t1/2 195 h, F 60% t1/2 14 h, F 65% Scheme 29.1 Aldehydes and derivatives thereof as drugs.

30 Ketones

Ketones are less electrophilic and chemically reactive than aldehydes, and can be highly orally available and long-lived in human plasma. This functional group is, however, often the weakest point in a molecule. The rate of metabolic transformation depends on the electronic properties of the substituents at the ketone carbonyl group. The more electron donating and sterically demanding the substituents, the higher will be the metabolic stability of a ketone. Benzophenones and alkanoyl benzenes are particularly stable. A selection of therapeutic ketones is sketched in Scheme 30.1 (see also Table 30.1).

OH Ph O O O Cl S N N O H MeO N F O MeO Acetohexamide Haloperidol Donepezil t1/2 1 h t1/2 18 h t1/2 75 h F 60% F 100% O NH2 N OH Ph O O O O Cl S N O Ph Ph O O MeO Nabumetone Tenidap Methadone Warfarin (log P 3.4; PSA 26) (log P 3.0; PSA 68) t1/2 24 h t1/2 35 h rapidly metabolized F 89% F 92% t1/2 37 h; F 93% to arylacetic acid

Scheme 30.1 Ketones as drugs.

The different rates of metabolic degradation of warfarin and nabumetone are remarkable. Warfarin is metabolized rather slowly by aromatic hydroxylation and α-hydroxylation and reduction of the ketone. In nabumetone, despite its similarity to warfarin, the ketone functionality is quickly degraded to an arylacetic acid. This

could be due to the higher lipophilicity and lower polar surface area (PSA) of nabumetone, which should increase its afﬁnity to liver enzymes and increase its rate of oxidative metabolization. Ketones are sometimes produced in vivo by oxidation of secondary alcohols or reactive methylene groups. The latter may therefore serve as prodrugs of ketones. One such instance is the oral contraceptive desogestrel, which is metabolized to the active ketone etonogestrel (Scheme 30.2).

HO HO

H CYP2C9 H

H H H H O

Desogestrel Etonogestrel − t1/2 short; F low t1/2 24 30 h (62−75% of etonogestrel on oral F 82% administration of desogestrel)

Scheme 30.2 Metabolism of desogestrel.

Some acetals or aminals of ketones can also be sufﬁciently stable to serve as drugs, as illustrated by the examples in Scheme 30.3. Particularly stable are acetals of ketones with an α-heteroatom (O, S, N, halogen), or with positive charges close to the acetal, which destabilize the intermediate carbocation required for the acid- mediated hydrolysis. Other condensation products of ketones that can be found in drugs include hydrazones, oximes, and enol ethers.

O O N O N H2N N O O N O Cl Cl NH2 O N N S N Guanadrel N N t1/2 11 h, F 85% N Zotepine Itraconazole Cl − t1/2 21 h, F 7 13% t1/2 21 h, F 55%

O MeO N CO2H O N N NH N H 2 N OH F3C Eltrombopag Fluvoxamine − − − t1/2 21 32 h, F 50% t1/2 12 30 h, F 50 60%

Scheme 30.3 Ketone derivatives as drugs. 30 Ketones 141

Table 30.1 Ketones, lactones, and related compounds. V in l kg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

1/ . ∗ t 2 5h V 2 6 CYCLOHEXANONE ± ∗∗ O F –CL274 dog pb – Mwt 98.1 Metabolites: cyclohexanol < ∗ 2 1/ ur 1% PSA 17.1 A˚ (t 2 4.8 h), 1,2-cyclohexanediol 1/ log P 0.82 (t 2 16 h), 1/ 1,4-cyclohexanediol (t 2 18 h)

1/ O t 2 0.3 h (iv) V 3.1 IROFULVEN HO F – CL 140 Antineoplastic pb 51–52% Mwt 246.3 Metabolism: isomerization to ur 0% PSA 57.5 A˚ 2 3-(2-hydroxyethyl)phenol, log P 1.13 hydroxylation of both vinylic CH3 OH groups

t1/ 23±4h V/F 0.79±0.38 NABUMETONE O 2 F 35% CL/F 0.37±0.25 Prodrug for methoxynaphthylacetic pb >99% Mwt 228.29 acid, all values given for ur 50% PSA 26.3 A˚ 2 acid upon oral dosing of prodrug MeO log P 3.40

1/ . ± . Cl t 2 62–80 h V 0 6 0 2 ATOVAQUONE F 47% CL 0.15 Antiprotozoal pb >99% Mwt 366.8 No metabolites known; O ur Negligible PSA 54.4 A˚ 2 excreted unchanged in bile log P 6.18 H OH O

1/ O t 2 12–13 h V – IDEBENONE MeO F Low CL – Nootropic pb 96% Mwt 338.4 Metabolism: oxidative OH MeO ur Negligible PSA 72.8 A˚ 2 degradation of side chain, O log P 3.91 reduction to hydroquinone

1/ . ± . O t 2 3 4 1 2h V – TEPRENONE F – CL – Gastroprotective pb – Mwt 330.6 ur – PSA 17.1 A˚ 2 log P 7.61

1/ t 2 2h(iv) V – COUMARIN F 1–3% CL – Flavor; extensive ﬁrst-pass pb 86% Mwt 146.1 metabolism to 7-hydroxycoumarin O O ur Low PSA 26.3 A˚ 2 and 2-hydroxyphenylacetic acid, log P 1.39 then glucuronidation (continued overleaf ) 142 30 Ketones

1/ t 2 1.4–3.2 h V 0.5–3.2 METHOXSALEN, F Low CL 10–157 8-METHOXYPSORALEN pb 80–90% Mwt 216.2 Photosensitizer, 2 O O O ur Negligible PSA 48.7 A˚ pigmentation agent OMe log P 1.52 Metabolism: oxidative ring opening of furan to arylacetic acid, demethylation

1/ O t 2 31–69 h V – FLUINDIONE F High CL – Anticoagulant F pb 99% Mwt 240.2 Metabolism: hydroxylation ur 35% PSA 34.1 A˚ 2 O log P 3.42

1/ O t 2 15 h V – OXAZIDIONE F – CL – Oral anticoagulant N O pb High Mwt 321.4 ur – PSA 46.6 A˚ 2 O log P 1.08

1/ t 2 54 h V 0.1–0.5 NITISINONE, NTBC OH O NO2 F High CL 0.07 Treatment of tyrosinemia, pb – Mwt 329.2 herbicide ur – PSA 97.0 A˚ 2 Metabolism: cleavage to

O CF3 log P 0.99 2-nitro-4-triﬂuoromethylbenzoic acid, hydroxylation of cyclohexane

1/ t 2 0.9–1.3 h V – MESOTRIONE OH O NO2 F >95% (rat) CL – Herbicide pb – Mwt 339.3 ur 49–72% PSA 140 A˚ 2 O S log P −0.99 O O

t1/ 90–140 h V 0.18 PHENPROCOUMON OH 2 F 100% CL – Anticoagulant pb 99% Mwt 280.3 Metabolism: glucuronidation, ur 2% PSA 46.5 A˚ 2 aromatic 4-, 6-, and O O log P 4.64 7-hydroxylation

1/ . ± . O t 2 30–40 h V 0 14 0 06 WARFARIN F 93±8% CL 0.05±0.02 Anticoagulant, CYP2C9 substrate OH pb 99±1% Mwt 308.33 Metabolism: aromatic and ur <2% PSA 67.51 A˚ 2 benzylic hydroxylation log P 3.03 O O 30 Ketones 143

1/ t 2 3–9 h V 0.1–0.3 ACENOCOUMAROL, O F 83% CL/F 2NICOUMALONE pb 99% Mwt 353.3 Anticoagulant OH ur <0.2% PSA 109 A˚ 2 Metabolism: reduction to log P 2.97 aniline, then N-acetylation, reduction of ketone to alcohol, O O NO2 aromatic hydroxylation of chromenone

1/ OH t 2 107–140 h V 0.49 (dog) TECARFARIN ∗ ∗ CF3 F 80–90% CL – rat CF3 pb 99% Mwt 460.3 Anticoagulant (same mechanism O ˚ 2 O O ur – PSA 72.8 A as warfarin) O log P 7.40 Metabolism: ester hydrolysis

1/ OH t 2 5–6 h V 0.1 TIPRANAVIR F 42% (rat) CL 0.3 Antiviral pb >99% Mwt 602.7 Metabolite: glucuronide CF3 O O ur 0.5% PSA 114 A˚ 2 HN S N log P 6.92 O O

1/ OH OH t 2 7–100 h V – DICOUMAROL F – CL – Vitamin K antagonist, pb >99% Mwt 336.3 anticoagulant ur <1% PSA 93.1 A˚ 2 O O O O log P 2.05

31 Carboxylic Acids

With a pKa of 3–5 in water, carboxylic acids are deprotonated and negatively charged in most parts of the body, excluding the stomach. The carboxyl group is an important pharmacophore of many drugs: fibrates, statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, and β-lactam and quinolone antibacterials contain essential carboxyl groups (Tables 31.1, 31.2). These compounds are usually well absorbed, but have low volumes of distribution (poor distribution in body tissues), and few cross the blood–brain barrer (bbb). Their volume of distribution is generally much smaller than that of amines, because negatively charged carboxylate groups show little affinity to the negatively charged phospholipid bilayers. The metabolic degradation of carboxylic acids (usually acyl glucuronidation or amidation) is slow, as illustrated by the long-lived drugs in Scheme 31.1.

Cl NH2 O O F CO2H S O CO H CO H 2 N 2 N N HN F

F Valproic acid Laropiprant Sparfloxacin t 1/2 14 h t 1/2 17 h t 1/2 18 h F 90% F 71% F 90%

O CO2H O CO2H N CO H Cl 2 Cl N O Cl

Oxaprozin Benoxaprofen Ciprofibrate − t 1/2 23 h t 1/2 27 35 h t 1/2 81 h F 95% F > 95% F 80%

Scheme 31.1 Carboxylic acids as drugs.

Drugs may also contain carboxyl groups not as pharmacophore but only to increase solubility and polarity. With lipophilic leads such an increase of polarity

N N

CO2H N N

CO2H O O Triprolidine Acrivastine Doxepin Olopatadine t 1/2 5 h t 1/2 2.5 h t 1/2 17 h t 1/2 10 h F 4% F 80% F 27% F 57% (nasal)

Scheme 31.2 Effect of the carboxyl group on pharmacokinetic (PK) properties.

31.1 Metabolism

Common metabolic transformations of carboxyl groups are activation by thioester formation with coenzyme A, followed by acylation of glycine, glutamine, or other amino acids [1]. Esteriﬁcation of carboxylic acids with glucuronic acid is mediated by uridine diphosphate glucuronosyltransferases, enzymes which also glucuronylate phenols, alcohols, thiols, and amines. These enzymes are mainly located in the liver and also in the intestine, kidneys, brain, and skin. Fatty acids or related compounds often undergo oxidative degradation to carboxylic acids of lower molecular weight. All these transformations can also occur with carboxylic acids formed by phase I metabolism of other functional groups. Illustrative examples of the metabolic fate of carboxylic acids are given in Scheme 31.3.

O O OH OH in vivo N H O

Benzoic acid Hippuric acid (conjugate with glycine)

H O MeO NH HO OH HO N 2 NH in vivo 2 O O CO H MeO HO HO 2 OMe OMe OMe Mescaline Conjugate with glutamine t 1/2 6 h

Scheme 31.3 Metabolism of carboxylic acids. 146 31 Carboxylic Acids

HO2C OH O OH O OH in vivo OH H OH (via allylic H O O alcohol) H H OH O O H Tetrahydrocannabinol H t 1/2 32 h, F 8% O Acyl glucuronide of THC-oic acid O O

HN OH HN OH in vivo Cl Cl NS NS O O O O Tianeptine Main metabolite t 1/2 3 h, F 99% t 1/2 5 h

Scheme 31.3 (Continued).

31.2 Bioisosteres of Carboxylic Acids

If the carboxyl group of a lead is metabolized too quickly, a metabolically more resistant bioisostere may be tested. Various functional groups are similarly acidic as carboxylic acids but sometimes more resistant to metabolic derivatization [2]. These include sulfonic acids, phosphonic acids, hydroxamic acids, N-acylcyanamides, N-acylsulfonamides, and tetrazoles. Imides and ureides (N-acylureas) are not acidic enough to act as carboxylic acid bioisostere (Scheme 31.4). Hydroxamic

O O O O O O O N N N S N R OH R N R N R R N R R N H H H H Carboxylic acid N-Acylcyanamides Imides, ureides N-Acylsulfonamides Tetrazoles − − − − − pKa 3 5 pKa 3 4 pKa 9 11 pKa 2 5 pKa 4 6

O O O O O N CO H S OH S 2 N NH2 H Cl

OMe Adrafinil Modafinil Indomethacin − t 1/2 1 h, F 80% t 1/2 10 12 h t 1/2 2.4 h, F 98%

Scheme 31.4 Bioisosteres of carboxylic acids. 31.3 Amino Carboxylic Acids, N-Acyl Amino Acids, and Related Compounds 147

O H N N OH O-Demethylation metabolism N−O bond cleavage O Debenzoylation Cl Glucuronidation Oxametacine No hydrolysis to indomethacin t 1/2 11 h OMe O O O O S HO O O N H

O CF3 O HO OH HO OH Travoprost Sulprostone − t 1/2 0.3 1.4 h (acid) t 1/2 2 h

N N NH N O 2 N N N N N N NH HO N N H H H N NH2 N O

O O F HO O HO O Methotrexate ZD 9331 − t 1/2 7 h; F 70% t 1/2 2 6 d; F 80% (dog)

Scheme 31.4 (Continued). acids are metabolically unstable, but may serve as prodrugs of amides (e.g., adraﬁnil as prodrug of modaﬁnil) or of carboxylic acids (e.g., ibuproxam as prodrug of ibuprofen). Oxametacine, however, is not a prodrug but a real bioisostere of indomethacin.

31.3 Amino Carboxylic Acids, N-Acyl Amino Acids, and Related Compounds

Amino acids show minimal solubility in water at their isoelectric point, that is, at the pH where an internal salt is formed and the molecule has no net electric charge. In contrast to peptides, low-molecular-weight amino acids are orally bioavailable, and some even cross the bbb. Many of these hydrophilic molecules undergo little metabolism and are mostly assimilated or excreted unchanged in urine. Unnatural analogs of amino acids can be antimetabolites or prodrugs, agonists, or antagonists of natural amino acids, including those that act as neurotransmitters (γ-aminobutyric acid (GABA), glycine, glutamic acid, and aspartic acid) (Table 31.2). 148 31 Carboxylic Acids

References

1. Stachulski, A.V., Harding, J.R., Lindon, J.C., Maggs, J.L., Park, B.K., and Wilson, I.D. (2006) Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis. J. Med. Chem., 49, 6931–6945. 2. Meanwell, N.A. (2011) Synopsis of some recent tactical applications of bioisosteres in drug design. J. Med. Chem., 54, 2529–2591.

Table 31.1 Carboxylic acids, esters, and amides, and hydroxamic acids. V inlkg−1; CL in ml min−1 kg−1; Mwt in g mol−1.

1/ ± . ± . t 2 14 3h V 0 22 0 07 VALPROIC ACID F 90±10% CL 0.11±0.02 Anticonvulsant, antimigraine, CO H 2 pb 93±1% Mwt 144.2 antimanic; Metabolism: ur 1.8±2.4% PSA 37.3 A˚ 2 dehydrogenation (single, to 1/ log P 2.58 2-propyl-2-pentenoic acid (t 2 1–2 d), and twofold), 3-hydroxylation

1/ t 2 2–3 h (iv) V 0.1–0.2 ARUNDIC ACID CO2H F – CL 0.7–1.0 Astrocycte modulating agent pb 99% Mwt 186.3 for treatment of stroke ur – PSA 37.3 A˚ 2 log P 4.31

1/ t 2 2–4 h V – ISOVALERAMIDE O F High CL – Anticonvulsant pb Negligible Mwt 101.2 NH 2 ur <4% PSA 43.1 A˚ 2 log P 0.67

1/ O t 2 6–10 h V – VALNOCTAMIDE F – CL – Antiepileptic

NH2 pb – Mwt 143.2 No metabolism to acid ur – PSA 43.1 A˚ 2 log P 1.89

1/ t 2 3.4 h V 0.2–0.4 DICHLOROACETIC ACID Cl CO2H F – CL 2–5 Caustic, keratolytic, pb – Mwt 128.9 topical astringent Cl ur <2% PSA 37.3 A˚ 2 Metabolism: hydrolysis to log P 0.67 glyoxylate

1/ t 2 90–100 h V – TRICHLOROACETIC ACID Cl CO2H F – CL – Metabolite of chloral, Cl pb 82–87% Mwt 163.4 hemostatic, caustic for Cl ur 93% PSA 37.3 A˚ 2 chemical skin peeling log P 1.73 149

1/ t 2 0.5–1.0 h V 0.2–0.4 4-HYDROXYBUTYRIC ACID F 25% CL – (Na-salt: OXYBATE SODIUM) < HO CO2H pb 1% Mwt 104.1 Sedative, narcotic ur <5% PSA 57.5 A˚ 2 Metabolism: oxidation to log P −0.76 succinic acid

1/ t 2 12 min V – DIMETHYL FUMARATE κ O F – CL – NF- B activation inhibitor MeO pb – Mwt 144.1 for the treatment of multiple OMe ur – PSA 52.6 A˚ 2 sclerosis O log P 0.43 Metabolite: monomethyl fumarate 1/ (t 2 36 h)

1/ t 2 0.8 h V 0.2 4-PHENYLBUTYRIC ACID F 78% CL 4 Treatment of hyperammonemia pb 81% Mwt 164.2 (urea cycle disorders) CO H 2 ur – PSA 37.3 A˚ 2 Metabolism: oxidative degradation 1/ log P 2.31 to phenylacetic acid (t 2 1.2 h, pb 56%) and N-phenylacetylglutamine 1/ (t 2 2.4 h)

1/ N t 2 1.2 h (iv) V 0.5 PIRMAGREL N F – CL 5 Thromboxane synthase CO2H pb – Mwt 232.3 inhibitor ur – PSA 54.6 A˚ 2 log P 2.11

1/ Cl t 2 4h V – PROGABIDE F 60% CL – GABA analog N CONH2 pb 98% Mwt 334.8 Metabolism: hydrolysis of ur – PSA 75.7 A˚ 2 amide and imine OH log P 3.14

1/ t 2 10–11 h V – TERBOGREL F – CL Thromoboxane A receptor N CO H 2 2 pb – Mwt 405.5 and synthase inhibitor CN ur – PSA 110 A˚ 2 N log P 3.95 N N H H

1/ t 2 6–9 h V 0.1–0.2 RIDOGREL F 90% CL – Antithrombotic, thromboxane N N CO2H O pb 60% Mwt 366.3 A2 synthase inhibitor ur – PSA 71.8 A˚ 2 log P 3.63

CF3

(continued overleaf ) 150 31 Carboxylic Acids

1/ t 2 22 h V 0.04 SERATRODAST O ∗ ∗ F 89% CL 0.2 monkey; thromboxane A2 pb >96% Mwt 354.4 antagonist, antiasthmatic ur – PSA 71.4 A˚ 2 Metabolism: glucuronidation, CO H 2 log P 4.63 reduction to hydroquinone, then O glucuronidation or sulfation, oxidative degradation of alkylene chain, hydroxylation of methyl

1/ O t 2 8–17 h V 2–4 FENBUFEN F – CL – NSAID > CO2H pb 99% Mwt 254.3 Metabolism: reduction of ur <2% PSA 54.4 A˚ 2 ketone to alcohol, oxidative log P 3.12 degradation to biphenylylacetic acid

1/ t 2 4–10 h V 25–89 CARGLUMIC ACID NH2 F –CL88CarbamoylphosphateI HN O pb – Mwt 190.2 synthase activator for ur 9% PSA 130 A˚ 2 treatment of hyperammonemia HO C CO H 2 2 log P −0.74

1/ t 2 42 h (rat) V – PROGLUMIDE F – CL – Cholecystokinin antagonist, pb – Mwt 334.4 anticholinergic ur – PSA 86.7 A˚ 2 Metabolism: N-depropylation HN O log P 2.69 N CO2H O

1/ t 2 1–5 h V – MITIGLINIDE F –CL–KATP channel blocker, O pb – Mwt 315.4 antidiabetic H ur – PSA 57.6 A˚ 2 Metabolism: acyl N CO H 2 log P 2.73 glucuronidation

1/ ± . ± . t 2 23 2h V 0 19 0 05 OXAPROZIN F 95–100% CL 0.035±0.007 Antiinﬂammatory O CO2H pb 99.5% Mwt 293.3 Metabolism: glucuronidation, ur <1% PSA 63.3 A˚ 2 hydroxylation of phenyl N log P 3.15 groups 151

1/ t 2 7–8 h V 0.23 CILOMILAST

CO2H F 100% CL 0.5 Antiasthmatic pb 99.5% Mwt 343.4 Metabolism: glucuronidation, O ur <1% PSA 79.6 A˚ 2 3-hydroxylation of CN log P 3.30 cyclopentyl, O-decyclopentylation MeO

t1/ 1.3±0.9h V 0.29±0.21 CHLORAMBUCIL Cl 2 F 87±20% CL 2.6±0.9 Antineoplastic N pb 99% Mwt 304.2 Metabolism: oxidative ur <1% PSA 40.5 A˚ 2 degradation to arylacetic CO2H Cl log P 2.61 acid, substitution of Cl by OH

1/ t 2 0.5 h V 0.24–0.32 BENDAMUSTINE Cl F – CL 7.5 Antineoplastic N N pb >95% Mwt 358.3 Metabolism: substitution CO2H ur 10–45% PSA 58.4 A˚ 2 of Cl by OH, N-demethylation, N Cl log P 2.38 conjugation with glutathione, hydroxylation of propylene

1/ . ± . . ± . t 2 1 4 0 2h V 0 5 0 2 MELPHALAN Cl CO2H F 71±23% CL 5.2±2.9 Antineoplastic NH pb 90±5% Mwt 305.2 Metabolism: sequential N 2 ur 12±7% PSA 66.6 A˚ 2 displacement of chloride Cl log P 0.54 by hydroxide

1/ t 2 10–13 d V – SENICAPOC, ICA-17043 O NH2 F – CL – Gardos channel inhibitor for pb – Mwt 323.3 treatment of sickle ˚ 2 Ph ur – PSA 43.1 A cell disease F F log P 3.97

1/ t 2 14–17 h V – AMBRISENTAN N F 80% CL – Endothelin antagonist, HO2C O pb 99% Mwt 378.4 antihypertensive MeO N ur 3.3% PSA 81.5 A˚ 2 Metabolism: hydroxylation of log P 6.24 methyl groups at pyrimidine; glucuronidation

1/ ± ∗ / . ∗ t 2 199 75 h V F 0 16 NAVEGLITAZAR F 100%∗ CL/F 0.16∗∗monkey OPh pb >99%∗ Mwt 422.5 PPAR-α/γ agonist, antidiabetic ur 0%∗ PSA 74.2 A˚ 2 Metabolism: racemization, CO2H O log P 4.81 dehydrogenation to OMe methoxycinnamic acid, O 4-hydroxylation of phenoxy group, then sulfation (continued overleaf ) 152 31 Carboxylic Acids

1/ ∗ t 2 68–124 h V 0.5 RAGAGLITAZAR F 68–93%∗ CL 2.3∗∗rat O pb – Mwt 419.5 PPAR-α/γ agonist, ur 0% PSA 68.2 A˚ 2 antidiabetic; discontinued N CO2H log P 3.88 because of cancerogenicity OMe O

1/ O t 2 45 h V 0.14 TESAGLITAZAR S F 100% CL 0.04 PPAR-α/γ agonist, O O CO2H pb 99.9% Mwt 408.5 antidiabetic 2 O ur 20% PSA 108 A˚ Metabolism: glucuronidation O log P 2.64

1/ . ∗∗ t 2 19–27 h V 0.5–1 7 MURAGLITAZAR F 79%∗ CL 12–14∗∗∗ ∗monkey ∗∗rat ∗∗∗estimate Ph pb – Mwt 516.5 PPAR-α/γ agonist, antidiabetic N CO2H O ur <4% PSA 111 A˚ 2 Metabolism: glucuronidation, OMe N log P 5.59 O-demethylation,

O O O O-dealkylation, hydroxylation of oxazolyl-CH2R, 4-hydroxylation of phenyl group

1/ t 2 1–2 h V –ORLISTAT F <1% CL – Pancreatic lipase inhibitor, pb 99% Mwt 495.7 antiobesity agent O ur <2% PSA 81.7 A˚ 2 Metabolism: lactone hydrolysis, O O log P 7.00 ester hydrolysis O HN O

1/ t 2 4–15 h V 0.3 FUSIDIC ACID F 91% CL Antibiotic CO H H 2 pb 98–99% Mwt 516.7 Metabolism: oxidation of HO 2 ur <0.1% PSA 104 A˚ allylic CH3 groups, O log P 5.76 glucuronidation

H O HO H

1/ ± t 2 17 10 h V – ADAPALENE CO2H F Low CL – Retinoid for treatment of acne pb >99% Mwt 412.5 Metabolism: O-demethylation, ur – PSA 46.5 A˚ 2 hydroxylation MeO log P 8.21 153

t1/ 17–22 h V 3.6 MYCOPHENOLIC ACID O OH 2 F 71–100% CL 2.8 Immunosuppressant CO H pb 98.7% Mwt 320.3 Metabolism: glucuronidation O 2 ur <1% PSA 93.1 A˚ 2 OMe log P 3.84

1/ ± / t 2 14 5h V F 7 ISOTRETINOIN F 25% CL/F 5.5±2.8 Antiacne agent pb 99.9% Mwt 300.4 Metabolite: acyl glucuronide ur <1% PSA 37.3 A˚ 2 CO2H log P 6.26

1/ . ∗ t 2 0.6–1.0 h V 1 1 TRETINOIN F 50% CL – ∗calculated CO2H pb – Mwt 300.4 Acid form of vitamin A ur – PSA 37.3 A˚ 2 log P 6.26

1/ t 2 50–60 h V 10.2 ACITRETIN CO H F 60% CL – Metabolite of etretinate, 2 pb – Mwt 326.44 antipsoriatic MeO ur >99% PSA 46.5 A˚ 2 Metabolism: trans–cis log P 6.00 isomerization

1/ . ± . O t 2 1 1 0 4h V – EPALRESTAT F – CL – Aldose reductase inhibitor CO2H N pb 90% Mwt 319.4 Metabolism: aromatic S ur – PSA 115 A˚ 2 hydroxylation S log P 2.02

1/ t 2 21–32 h V 0.13 ELTROMBOPAG F 50% CL 0.18 Trombopoetin agonist pb 99% Mwt 442.5 Metabolism: oxidation, CO2H ur 0% PSA 115 A˚ 2 glucuronidation O N OH log P 3.71 N H N N

1/ t 2 4h V – CINCHOPHEN CO2H F High CL – Analgesic, induces ulcers, pb – Mwt 249.3 hepatotoxic ur <5% PSA 50.2 A˚ 2 Metabolism: aromatic N log P 4.18 hydroxylation

(continued overleaf ) 154 31 Carboxylic Acids

1/ . ± . t 2 13–18 h V 0 24 0 08 BREQUINAR CO2H F High CL 0.5±0.2 ∗iv F pb >98% Mwt 375.4 Immunosuppressant ur 0.1–6%∗ PSA 50.2 A˚ 2 F N log P 6.69

1/ . ± . . ± . t 2 1 1 0 2h V 0 14 0 03 GEMFIBROZIL F 98±1% CL 1.7±0.4 Antilipemic pb 97–99% Mwt 250.3 Metabolism: hydroxylation CO2H O 2 ur <1% PSA 46.5 A˚ and oxidation to CO2Hof log P 4.30 aromatic 3-methyl group

1/ t 2 4–6 h V 0.2 EFAPROXIRAL, RSR-13 O CO H < O 2 F CL 1 Allosteric modiﬁer pb 95% Mwt 341.4 of hemoglobin N ur PSA 75.6 A˚ 2 Metabolism: glucuronidation H log P 3.35

t1/ 1.5–3.0 h V 0.24–0.35 BEZAFIBRATE O CO2H 2 O F 100% CL 1.4 Antilipemic N pb 95% Mwt 361.8 Metabolism: glucuronidation H ˚ 2 Cl ur 35–40% PSA 75.6 A log P 2.50

1/ . ± . t 2 81 h V 0 15 0 02 CIPROFIBRATE O CO H 2 F 80% CL 0.02 Antilipemic Cl pb 99% Mwt 289.2 Metabolism: glucuronidation ˚ 2 Cl ur 7% PSA 46.5 A log P 2.93

t1/ 13±3h∗ V/F 0.11±0.02∗ CLOFIBRATE O 2 F 95±10%∗ CL/F 0.12±0.01∗∗acid on oral dosing of ester O ∗ O pb 97% Mwt 242.7 Antilipemic; ur 57±2%∗ PSA 35.5 A˚ 2 prodrug of CPIB Cl log P 3.88

t1/ 18±10 h∗ V – BECLOBRATE O 2 F –CL0.5∗acid on oral dosing of ester Cl O O pb >90%∗ Mwt 346.9 Antihyperlipoproteinemic ur Low PSA 35.5 A˚ 2 Metabolism: fast hydrolysis log P 6.00 of ester, glucuronidation 155

1/ ∗ . ∗ O t 2 20–27 h V 0 9 FENOFIBRATE ∗ . ∗ ∗ Cl O F 60% CL 0 17 acid on oral dosing of ester O pb >99%∗ Mwt 360.8 Antilipemic, prodrug; ester is not ur Negligible PSA 52.6 A˚ 2 detectable in plasma O log P 5.80 Further metabolism: glucuronidation

1/ t 2 2h V – MK-473 O CO2H F –CL–Diuretic, uricosuric, pb – Mwt 357.2 antihypertensive Cl ur <10% PSA 63.6 A˚ 2 Metabolism: cyclopentyl O Cl log P 3.81 hydroxylation, then oxidation to ketones

1/ t 2 6h V 0.1 TIENILIC ACID, TICRYNAFEN O CO2H F –CL–Diuretic, uricosuric, pb 95–98% Mwt 331.2 antihypertensive S Cl ur – PSA 91.8 A˚ 2 Metabolism: aromatic O Cl log P 3.04 hydroxylation, S-oxidation to electrophilic thiophene S-oxide; withdrawn in 1982 for inducing autoimmune hepatitis

1/ t 2 2–4 h V 0.26 ETHACRYNIC ACID O CO2H F 7–35% CL 8.7 Diuretic > Cl pb 98% Mwt 303.1 Active metabolite: addition product ur – PSA 63.6 A˚ 2 to cysteine O Cl log P 2.84

1/ t 2 5h V 0.1–0.2 TRICLOPYR Cl Cl F –CL0.3∗dog pb 94–99%∗ Mwt 256.5 Herbicide ˚ 2 Cl N O CO2H ur 80% PSA 59.4 A log P 2.35

1/ t 2 5–14 h V 0.5 BILASTINE O ∗ ∗ N F 25–69% CL 4.6 animals N pb 85% Mwt 463.6 Histamine H1 antagonist ur 33% PSA 62.7 A˚ 2 No metabolism in humans N log P 5.06 CO2H

1/ ∗ O t 2 24–48 h V – HALOFENATE H ∗ F High CL – acid on oral dosing of ester F3C O N O pb >99%∗ Mwt 415.8 Prodrug of halofenic acid O ur 39%∗ PSA 64.6 A˚ 2 log P 3.77

(continued overleaf ) 156 31 Carboxylic Acids

1/ . ± . O CO2H t 2 0.7–2.9 h V 0 85 0 09 SULOTROBAN O O F –CL10Thromboxane A2 antagonist S N pb – Mwt 335.4 H ur 52–62% PSA 101 A˚ 2 log P 1.38

1/ t 2 7h V – DALTROBAN O O CO2H F High CL – S Thromboxane A2 antagonist N pb – Mwt 353.8 H ˚ 2 Cl ur 40% PSA 91.9 A log P 2.68

1/ t 2 2–3 h V – RAMATROBAN CO H N 2 F 100%∗ CL 12∗ *dog O O pb >95% Mwt 416.5 Prostaglandin (PGD2,PGH2)and S 2 N ur <8% PSA 96.8 A˚ thromboxan (TxA2) antagonist H log P 3.02 Metabolism: acyl glucuronidation F

t1/ 22 h V 4.4 IFETROBAN CO2H 2 F 48% CL 6.4 Thromboxane antagonist O O pb – Mwt 440.5 Metabolism: acyl glucuronidation ur Low PSA 102 A˚ 2 N HN log P 2.49 O

1/ t 2 1–2 h V 0.5 VORINOSTAT F 43% CL 28 Histone deacylase inhibitor for O H pb 71% Mwt 264.3 treatment of cutaneous T-cell N OH N ur Negligible PSA 78.4 A˚ 2 lymphoma H O log P 0.86 Metabolism: O-glucuronidation, oxidative degradation to succinoyl 1/ anilide (t 2 11 h)

1/ O t 2 11–31 h V 0.4 PANOBINOSTAT OH F 30% CL 7.3 Histone deacylase inhibitor N H pb – Mwt 349.4 Metabolism: reductive N−O bond N H ur – PSA 77.2 A˚ 2 cleavage, amide hydrolysis, log P 3.62 oxidative degradation of cinnamic acid, glucuronidation N H

1/ t 2 1–4 h V – TOSEDOSTAT F –CL–Orally available antineoplastic, O O H pb – Mwt 406.5 aminopeptidase inhibitor N OH 2 1/ O N ur – PSA 125 A˚ Active metabolite: acid (t 2 6–11 h) H O OH log P 2.24 157

t1/ 1h V – ADRAFINIL O O 2 F 80% CL – CNS stimulant S OH N pb – Mwt 289.4 Metabolism: N-deoxygenation to H ur – PSA 85.6 A˚ 2 modaﬁnil log P 0.77

t1/ 10–12 h V 0.9 MODAFINIL O O 2 F –CL1.3CNS stimulant, analeptic S Metabolism: hydrolysis to NH2 pb 62% Mwt 273.4 ur 10% PSA 79.4 A˚ 2 carboxylic acid log P 1.18 Armodaﬁnil = R-modaﬁnil 1/ (t 2 15 h)

Table 31.2 Amino acids, hydroxy acids, and related compounds. V inlkg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ t 2 4.9 h V 0.39 6-AMINOHEXANOIC ACID F –CL2.7ε-AMINOCAPROIC ACID

H2N CO2H pb 8% Mwt 131.2 Hemostatic ur 70–86% PSA 63.3 A˚ 2 Metabolism: oxidative deamination log P 0.03 to adipic acid

1/ NH t 2 1.2–2.3 h V 0.6–0.8 L-N-METHYLARGININE F – CL 8.0–9.5 Endogenous nitric oxide synthase CO H N N 2 pb Negligible Mwt 188.2 inhibitor H H ur <1% PSA 111 A˚ 2 Metabolism: hydrolysis of NH2 log P −0.08 guanidine to urea (citrulline)

1/ t 2 3–8 h V 0.34 EFLORNITHINE CO H 2 F 54% CL – Antineoplastic, antiprotozoal H2N F NH2 pb 0% Mwt 182.2 F ur 80% (iv) PSA 89.3 A˚ 2 log P 0.30

1/ ∗ O NH t 2 37 min (iv) V 0.3–0.5 BUTHIONINE SULFOXIMINE F 2%∗ CL 3–4 ∗mouse S CO2H pb – Mwt 222.3 Inhibits glutathione biosynthesis ˚ 2 NH2 ur 60% (iv) PSA 113 A log P 0.52 (continued overleaf ) 158 31 Carboxylic Acids

1/ ∗ t 2 0.5–1.0 h V 0.05–0.23 CALCIUM DISODIUM EDETATE, CO2Na CO2Na F <5% CL 0.8 CaNa2EDTA ∗ N pb 0% Mwt 288.2 iv N ur >95% PSA 167 A˚ 2 Chelator for heavy-metal poisoning O O O log P −4.65 O Ca

1/ . ± . . ± . O t 2 2 0 0 2h V 0 24 0 03 CARBOPLATIN O F –CL1.5±0.3 Antineoplastic H3N Pt pb 0% Mwt 371.3 2 H3N O ur 77±5% PSA 107.9 A˚ O log P −5.20

1/ H H t 2 25–27 h V 8.3–11.6 OXALIPLATIN N O O F – CL 2.2–2.4 Antineoplastic pb >90% Mwt 397.3 Pt ur 40–50% PSA 85.8 A˚ 2 N O O log P −4.96 H H

1/ t 2 5–12 h V – SATRAPLATIN H H F – CL 5.2–6.2∗ ∗monkey O O H N Cl pb 90–94% Mwt 500.3 Antineoplastic Pt ur 10% PSA 96.9 A˚ 2 Metabolism: reductive abstraction N Cl − . O O log P 3 18 of both acetoxy groups H H

1/ . ± . t 2 0 5 0 1h V 0.3 CISPLATIN F –CL6 Antineoplastic H N Cl 3 Pt pb >90% Mwt 300.1 H N Cl 3 ur 23±9% (iv) PSA 55.3 A˚ 2 log P −4.89

t1/ 33–76 h V 0.22 STIBOGLUCONATE CO2H CO2H 2 HO OH F –CL–Anthelmintic O O pb – Mwt 679.8 iv or im administration only Sb Sb HO O O O OH ur >80% PSA 276.3 A˚ 2 H O O H HO OH log P −5.34

1/ ± . ± . t 2 25 5d V 0 26 0 05 GOLD SODIUM THIOMALATE CO H F –CL7.0±0.6 AUROTHIOMALATE HO C 2 2 pb >95% Mwt 346.1 (Acid shown) S Au ur 70% PSA 74.6 A˚ 2 Antipruritic, treatment of log P −1.18 rheumatoid arthritis 159

1/ t 2 1.5–3.0 h V 0.9 PENICILLAMINE F 40–70% CL 10.7 Antirheumatic, chelating agent CO H HS 2 pb 80% Mwt 149.2 (copper) ˚ 2 NH ur 10–40% PSA 102 A Metabolism: disulﬁde formation 2 log P 0.85 with itself and cysteine, S-methylation

1/ t 2 1.0–1.5 h V – METHIONINE F 100% CL – Hepatoprotectant, antidote, urinary S CO2H pb – Mwt 149.2 acidiﬁer, nutritional supplement 2 NH2 ur 5–10% PSA 88.6 A˚ log P 0.22

1/ t 2 2–7 h V – OXITRIPTAN, HO F 50–85% CL 1.7–3.8 5-HYDROXYTRYPTOPHAN pb 60% Mwt 220.2 Prodrug of serotonin, CO2H ur – PSA 99.3 A˚ 2 antidepressant, antimigraine; log P −0.29 crosses bbb N NH2 Metabolism (in CNS): H decarboxylation, then oxidation to hydroxyindolylacetic acid

1/ . ± . . ± . t 2 1 4 0 4h V 1 7 0 4 LEVODOPA ± ± HO CO2H F 41 16% CL 23 4 Antiparkinsonian pb – Mwt 197.2 NH HO 2 ur <1% PSA 104 A˚ 2 log P −1.15

1/ . ± . . ± . t 2 1 8 0 6h V 0 46 0 15 METHYLDOPA HO CO2H F 42±16% CL 3.7±1.0 Antihypertensive pb 1–16% Mwt 211.2 NH2 HO ur 40±13% PSA 104 A˚ 2 log P −0.74

1/ t 2 2.1 h V – CARBIDOPA HO CO2H F 40–70% CL – Antiparkinsonian (in combination NH pb 76% Mwt 226.2 with levodopa); does not cross bbb HO H2N ur 30% PSA 116 A˚ 2 Metabolism: reductive N−Nbond log P −1.75 cleavage

1/ I t 2 5–7 d V 10 THYROXINE, T4 F 91% CL – Thyroid hormone HO I CO2H pb >99.9% Mwt 776.9 NH ur – PSA 92.8 A˚ 2 I O 2 log P 4.72 I

(continued overleaf ) 160 31 Carboxylic Acids

1/ O NH t 2 4–30 h V 0.2 CYCLOSERINE F 70–90% CL – Bacteriostatic, crosses bbb O pb <20% Mwt 102.1 ur 60–70% PSA 64.3 A˚ 2 NH2 log P −2.99

t1/ 10±4h(iv) V 0.5 ACIVICIN N O 2 Cl F –CL0.69Antineoplastic CO2H pb Negligible Mwt 178.6 H ur 14–19% (iv) PSA 84.9 A˚ 2 NH 2 log P −0.78

1/ . ± . . ± . t 2 0 8 0 1h V 0 20 0 03 CILASTATIN H F Low CL 3.0±0.3 Values for simultaneous N CO2H S pb 35% Mwt 358.5 administration with imipenem 2 O CO2H NH2 ur 70±3% PSA 155 A˚ Dipeptidase inhibitor log P 2.42

1/ . ∗∗ t 2 6–7 h V 0.6–0 9 ICOFUNGIPEN, PLD-118 CO H ∗ ∗∗ 2 F 60–100% CL 1.7–5.0 ∗animals pb <1% Mwt 141.2 ∗∗rabbit NH2 ur 70–90% PSA 63.3 A˚ 2 Antifungal log P −0.16

1/ t 2 3–7 h V 0.84 BACLOFEN NH2 F 95% CL 2.6 Muscle relaxant, GABA agonist CO2H pb 30% Mwt 213.7 Metabolism: deamination to ur 70–80% PSA 63.3 A˚ 2 4-hydroxy-3-arylbutyric acid Cl log P 0.78

t1/ 6.5±1.0h V 0.80±0.09 GABAPENTIN NH 2 2 F 60% CL 1.6±0.3 Antiepileptic pb 0% Mwt 171.2 CO2H ur 100% PSA 63.3 A˚ 2 log P 0.62

1/ t 2 2–3 h V 0.1–0.2 TRANEZAMIC ACID CO2H F 33–35% CL 1.6–1.8 TRANEXAMIC ACID pb 3% Mwt 157.2 Hemostatic (antiﬁbrinolytic); H N 2 ur >95% PSA 63.3 A˚ 2 crosses bbb log P 0.50

1/ ∗ . ∗ t 2 6–10 h V 0 4 OSELTAMIVIR H2N CO2Et F 75%∗ CL 4.8∗ Prodrug of acid, neuraminidase pb 3%∗ Mwt 312.4 inhibitor, antiviral HN ur 3% PSA 90.7 A˚ 2 ∗acid on oral administration of O O log P 1.71 ester 161

1/ t 2 5–7 h V 0.5 PREGABALIN > NH2 F 90% CL – Anticonvulsant pb 0% Mwt 159.2 CO2H ur 99% PSA 63.3 A˚ 2 log P 1.12

1/ t 2 4–8 h V 0.8 VIGABATRIN NH2 F 50–65% CL 1.7 Antiepileptic pb – Mwt 129.2 Racemate (only the S enantiomer is CO H 2 ur 50–70% PSA 63.3 A˚ 2 active) log P −0.10 Metabolism: lactam formation

1/ t 2 2–15 h V 0.26–0.82 CARNITINE OH F 9–25% CL 1.5–1.7 Antihyperlipoproteinemic pb 0% Mwt 147.2 Metabolite: trimethylamine N CO2H ur 70–80% PSA 60.4 A˚ 2 log P −5.56

1/ O t 2 2h V 1.8 ETOZOLIN F >90% CL – Diuretic N N pb – Mwt 284.4 Metabolism: hydrolysis of ester to CO Et 2 1/ S 2 ur – PSA 75.2 A˚ acid (ozolinon, t 2 6–10 h), then log P 2.75 glucuronidation

1/ t 2 1–2 h V 1.0–1.9 MOLSIDOMINE F 44–59% CL 11–17 Prodrug of nitrous oxide N O Metabolism: hydrolysis and O N N pb 3–11% Mwt 242.2 2 CO2Et ur <2% PSA 84.0 A˚ decarboxylation of carbamate, then N log P −3.32 rearrangement to N-morpholino-N- nitrosoaminoacetonitrile

1/ O t 2 1.5–2.0 h V – GABOXADOL F 84–93% CL 6.9 Hypnotic < NH pb 2% Mwt 140.1 Metabolism: O-glucuronidation 2 HN O ur 50–60% PSA 50.4 A˚ log P 0.71

1/ t 2 5–9 h V 1TIAGABINE CO2H S F 90% CL 3 Antiepileptic pb 96% Mwt 375.6 Metabolism (CYP3A4): N ur 2% PSA 97.0 A˚ 2 glucuronidation, thiophene log P 4.03 oxidation to 2-thiophenone S

1/ t 2 2h V 0.35 NEGAMYCIN OH NH2 O F –CL–Antibacterial H N N CO H 2 N 2 pb – Mwt 248.3 H ur – PSA 142 A˚ 2 log P −4.14 (continued overleaf ) 162 31 Carboxylic Acids

1/ t 2 0.6 h (iv) V 0.28 BETAMIPRON O F –CL9.2Antibacterial adjunct (renal

CO2H pb 83% Mwt 193.2 protection) N ˚ 2 H ur 40% PSA 66.4 A log P 0.93

1/ O t 2 26 h V –BIOTIN F –CL–Vitamin HN NH pb 80% Mwt 244.3 Metabolism: oxidation to sulfoxide, H H ur 40–76% PSA 104 A˚ 2 oxidative degradation of log P 0.86 4-carboxybutyl to 2-carboxyethyl CO H S 2 (bisnorbiotin)

t1/ 2h∗ V 0.55 N-ACETYLCYSTEINE CO H 2 HS 2 F 10% CL 3.1 ∗iv: 5.5 h HN O pb 83% Mwt 163.2 Mucolytic, high ﬁrst-pass ur 20–30% (iv) PSA 105 A˚ 2 metabolism (N-deacetylation) log P −0.70

1/ . ± . . ± . t 2 2 2 0 5h V 0 8 0 2 CAPTOPRIL F 65% CL 12.0±1.4 ACE inhibitor, antihypertensive HS N pb 30±6% Mwt 217.3 Metabolism: oxidative disulﬁde ± ˚ 2 O CO2H ur 38 11% PSA 96.4 A formation, S-methylation log P 0.27

t1/ 19–53 h V 5±2 TIOPRONIN H 2 F 63% CL 2.6 Antidote (heavy metals), mucolytic, N CO2H HS pb – Mwt 163.2 hepatoprotectant O ur – PSA 105 A˚ 2 Metabolite: mixed disulﬁde with log P −0.67 cysteine

t1/ 1–3 h V – ERDOSTEINE O 2 S F –CL41Active metabolites: S CO H N 2 pb 65% Mwt 249.3 N-acetylhomocysteine, O H ur – PSA 134 A˚ 2 homocysteine, hydrolyzed log P −0.32 thiolactone

t1/ 6–9 h V – VALROCEMIDE O 2 H F –CL1.3Anticonvulsant N NH2 pb – Mwt 200.3 Metabolites: N-valproylglycine, 2 O ur 10–20% PSA 72.2 A˚ valproic acid log P 1.02

1/ t 2 6–10 h V – TERUTROBAN F –CL–Antiplatelet agent, antithrombotic O O pb – Mwt 407.9 S ur – PSA 91.9 A˚ 2 N CO2H H log P 3.35 Cl 163

1/ t 2 1–2 h V 0.3 (rat) REBAMIPIDE F 5% CL 21±3 (rat) Antiulcerative NH pb 98% Mwt 370.8 Metabolism: 8-hydroxylation ur 10% PSA 95.5 A˚ 2 O O log P 2.56

N CO2H H Cl

1/ t 2 1.4–2.9 h V 0.13 NATEGLINIDE F 72% CL 1.5–2.0 Antidiabetic O Pb 97% Mwt 317.4 Metabolism: acyl glucuronidation, ur 13–16% PSA 66.4 A˚ 2 conversion of isopropyl group to N CO2H log P 2.35 isopropenyl, 1-hydroxy-iPr, H 2-hydroxy-iPr, and 1,2-dihydroxy-iPr

1/ t 2 10–15 h V 0.23 TOLRESTAT MeO Aldose reductase inhibitor for S F 68% (dog) CL 0.5 pb >99% Mwt 357.4 treatment of diabetic neuropathy ˚ 2 Metabolism: oxidation to S-oxide, F3C N CO2H ur 30–40% PSA 81.9 A log P 3.59 then to amide, O-demethylation, then O-sulfation; withdrawn in 1997 because of hepatotoxicity

32 Carboxylic Esters

Because of their metabolic lability, carboxylic esters are often used as prodrugs for carboxylic acids, phenols, or alcohols. Esters are more lipophilic than carboxylic acids, and esters of hydrophilic acids will usually be absorbed more readily from the gastrointestinal tract than the parent acid. Ethyl or methyl esters, or acetic acid esters of primary aliphatic alcohols are usually hydrolyzed in vivo within minutes and can hardly be detected in plasma (Scheme 32.1).

O O O N O O OH Ph O O O O H N H O O O Heroin Flavoxate Acetylsalicyclic acid t1/2 3 min (iv) t1/2 5 min t1/2 15 min F <35% F 100% F 68%

SPh CO2Et CO Me N 2 Ph N MeO2C H Ph S N N Ph N O CO H O O CO2H 2 O Benazepril Zofenopril Remifentanil t (ester) 0.7 h t (ester) 0.9 h 1/2 1/2 t 3−10 min (iv) t (diacid) 10−22 h t (thiol) 4.6 h 1/2 1/2 1/2 t (ester/acid) 2 h F 28−37% F 65−78% 1/2

O CO2Et N NH2 MeO2C H N O NH N HN 2 S H O NH H N O O 2 2 Articaine Oseltamivir NH Nafamostat − t1/2 25 min t1/2 short (acid: 6 10 h) t1/2 23 min t1/2 (acid) 2.4 h F 75% (acid on ester, po) F low Scheme 32.1 Carboxylic esters as drugs.

Some types of ester are, however, sufﬁciently stable to serve as drugs. Also, for topical or ophthalmic applications, where esterase activity is less intense, carboxylic esters can be sufﬁciently stable. Esters of tertiary alcohols or alcohols containing tertiary amines (e.g., denaverine) are particularly stable toward enzymatic hydrolysis. Similarly, esters with a carbonyl group in conjugation with electron-donating groups (e.g., vinylogous carbonates or carbamates, electron-rich arylcarboxylic or heteroarylcarboxylic esters), or esters of sterically crowded carboxylic acids, are resistant toward nucleophilic attack and less prone to hydrolysis in vivo [1] (Scheme 32.2).

O MeO O O O O O O N HO N S N N Ph Ph

L-Acetylmethadol Oxybutynin Diltiazem t 8−19 h t 2 h t 5−6 h 1/2 OMe 1/2 1/2 F 48% F 6% F 44% OMe O OMe H O Cl O O N MeO C CO Et O 2 2 NH 2 OMe N O H H N NH H O OMe

Denaverine Amlodipine Reserpine α β − t1/2 34 h (iv) t1/2 39 h t1/2 4.5 h; t1/2 150 250 h F 37% F 74% F 40−50%

Scheme 32.2 Metabolically resistant esters.

Lactones are chemically and enzymatically more labile than noncyclic esters because of the high-energy cis conformation of the alkoxycarbonyl group in lactones. However, ﬁve- and six-membered lactones will often be formed spontaneously from the corresponding hydroxy acids at neutral or slightly acidic pH. Accordingly, the metabolic hydrolysis of lactones is often reversible, for example, for the anti- inﬂammatory rofecoxib, for the statins, or for the tecans. β-Lactones are reactive acylating and alkylating agents that undergo irreversible ring opening.

Reference

1. Buchwald, P. and Bodor, N. (1999) Quantitative structure–metabolism relationships: steric and nonsteric effects in the enzymatic hydrolysis of noncongener carboxylic esters. J. Med. Chem., 42, 5160–5168. 166

33 Amides

Amides are a ubiquitous functional group in living organisms (peptides, proteins). Most unnatural amides are sufficiently stable to serve as oral drugs, and only rarely quick enzymatic hydrolysis occurs (Table 33.1). Amides that are chemically reactive toward nucleophiles, such as those derived from highly electrophilic carboxylic acids (e.g., trifluoroacetamides), will also undergo fast metabolic hydrolysis in vivo.If an amide resembles the final or first amide bond in a peptide with a positive or negative charge close to the amide bond, quick hydrolysis by an aminopeptidase or carboxypeptidase may occur (Scheme 33.1). Similarly, endopeptidases may cleave uncharged peptidomimetics. Peptidases are, however, highly selective, and most unnatural amides will not be substrates of these enzymes. As in esters and carbamates, steric shielding will also inhibit the enzymatic hydrolysis of amides.

Exopeptidases Aminopeptidases Carboxypeptidases

R O R O R O R H H H N N N O H3N N N N H H H O R O R O R O

Endopeptidases

Scheme 33.1 Metabolism of peptides.

The absorption of highly insoluble amines or alcohols from the gastrointestinal tract can be enhanced by acylation with glycine. Aminopeptidases present in the epithelium of the intestine will rapidly deacylate the prodrug and regenerate the active compound, as exempliﬁed by the benzodiazepine prodrug rilmazafone and the antihypotensive midodrine (Scheme 33.2).

O O N

H2N N N O H2N N O N H N Amino- N N peptidase N N N N N O O Cl Cl Cl N Cl Cl Cl Rilmazafone

OH OH H Amino- MeO N peptidase MeO NH2 NH2 O OMe OMe Desglymidodrine Midodrine t 3–4 h t 25 min 1/2 1/2 F 93% (drug on oral dosing of midodrine)

Scheme 33.2 Amides as prodrugs.

Acylation with glycine, alanine, or short peptides can be used to enhance solubility of a compound for a liquid, parenteral formulation (Scheme 33.3). A parenteral formulation may be useful even if the drug is orally bioavailable, for instance, if the drug is hepatotoxic or must be given to unconscious patients. Parenteral dosing also evades ﬁrst-pass metabolism and CYP (cytochrome P450) induction or inhibition. Amide-based prodrugs can also be used as slow-release formulations of short-lived drugs.

O O

F CO2H F CO2H

in vivo H N N N H N N N O H F few minutes F N H N N H2N 2 H H H O Alatrofloxacin F Trovafloxacin F (for parenteral administration) t 1/2 11 h, F 90%

Ph S N in vivo HS N CO2H O O N O OH O H O Alacepril Captopril t 1/2 5 h (captopril on t 1/2 2.2 h, F 65% oral dosing of alacepril)

Scheme 33.3 Peptides as prodrugs. 168 33 Amides

The metabolic stability of N-unsubstituted amides (RCONH2) is difﬁcult to predict. Sterically accessible, lipophilic amides are often hydrolyzed quickly, whereas hydrophilic or sterically shielded amides will be more stable. Some of the amides sketched in Scheme 33.4 have low oral bioavailabilities and half-lives because of amide-bond hydrolysis, but some closely related amides and esters are not extensively hydrolyzed to carboxylic acids.

OH O O NH2 O NH2 H2N NH NH2 N S 2 O O O O Nepafenac Modafinil Salicylamide Levetiracetam t 1/2 <1 h (of acid), F 6% (rat) t 1/2 10–12 h t 1/2 1–2 h, F <10% t 1/2 6–8 h, F 100% fast hydrolysis to acid hydrolysis to acid no hydrolysis to acid hydrolysis to acid O O CO H NH 2 2 Ph O HO N N N O O OEt H S N HN

S Metopimazine Normeperidine Alvimopan t 1/2 5 h, F 22% t 1/2 14–21 h t 1/2 10–17 h, F 1–19% hydrolysis to acid hydrolysis of ester hydrolysis of amide

O NH2 OMe OH N H O N NH2 N Cl NH O O N MeO 2

Aliskiren t 1/2 34–41 h Clocapramine F 2.6% t 1/2 46 h F 16% (dog)

Scheme 33.4 N-Unsubstituted amides as drugs.

N-Alkylamides may be dealkylated via C-hydroxylation followed by hemiaminal hydrolysis, similar to the oxidative dealkylation of amines. This metabolic transformation is often observed in lactams, such as benzodiazepines (Scheme 33.5), and in cyclic imides and ureides (e.g., in barbiturates). 33 Amides 169

O H O H O N N N OH in vivo in vivo Cl N Cl N Cl N

Diazepam Nordazepam Oxazepam t 1/2 43 h, F 100% t 1/2 73 h, F 99% t 1/2 8 h, F 97%

in vivo in vivo in vivo

F3C O O O N N N

Cl N Cl N Cl N

Halazepam Pinazepam Prazepam t 1/2 15 h t 1/2 1–5 h, F 40–50% t 1/2 1.3 h

Scheme 33.5 N-Dealkylation of benzodiazepines.

− Table 33.1 Amides. V inlkg−1;CLinmlmin−1 kg 1; Mwt in g mol−1.

1/ t 2 2.5 h V 2.1 DEET, AUTAN O F 48%∗ CL – ∗from dermal absorption N pb – Mwt 191.3 Insect repellant ur 10–14% PSA 20.3 A˚ 2 Metabolism: deethylation, log P 2.42 oxidation of CH3 to CO2H

1/ ∗ . ∗ t 2 14 d V 0.08–0 44 LEFLUNOMIDE F 82–94%∗ CL 0.007–0.012∗∗teriflunomide (see below) ∗ CF3 pb 99.4% Mwt 270.2 on oral dosing of O 2 ur Negligible PSA 55.1 A˚ leflunomide; antirheumatic, N O H log P 2.29 immunomodulator; N leflunomide is a prodrug of its active cyanoketone metabolite teriflunomide

1/ t 2 15–18 d V –TERIFLUNOMIDE CF F <40% CL – Dihydroorotate OH O 3 pb >99% Mwt 270.2 dehydrogenase inhibitor, N ur – PSA 73.1 A˚ 2 agent for multiple H CN log P 1.52 sclerosis; active metabolite of leﬂunomide (continued overleaf ) 170 33 Amides

1/ ∗ t 2 4–22 h V – FLUTAMIDE F –CL– ∗2-hydroxyisopropyl pb 94–96% Mwt 276.2 metabolite; Nonsteroidal ur Negligible PSA 74.9 A˚ 2 antiandrogen, prodrug of NO log P 3.52 the active 2-hydroxy- O 2 isopropyl metabolite; N CF Metabolism: single, twofold, H 3 and threefold hydroxylation of isopropyl group, reduction of nitro to amino, hydrolysis of amide, aromatic hydroxylation

t1/ 12–20 h V – ROFLUMILAST Cl 2 O N F 69–92% CL – PDE4 inhibitor, O pb 99% Mwt 403.2 bronchodilator F N H ur – PSA 60.5 A˚ 2 Metabolite: pyridine-N-oxide Cl F O log P 2.31

1/ . ∗ t 2 4h V 1 4 ANDARINE ∗ ∗∗ H F 38–91% CL 3–7 dog N NO O 2 pb – Mwt 441.4 Selective androgen receptor 2 O ur – PSA 105 A˚ modulator O N CF 3 log P 4.01 Metabolism: amide HO H hydrolysis (both), reduction of NO2 to NH2

t1/ 4h V – OSTARINE NC CN 2 O F – CL – Selective androgen receptor pb – Mwt 389.3 modulator O N CF3 HO H ur – PSA 106 A˚ 2 log P 2.93

1/ t 2 2–16 d V 1.2–1.3 BICALUTAMIDE F CN F 100% CL 0.8 Antiandrogen, hormonal O pb 96% Mwt 430.4 antineoplastic S N CF3 ur 0% PSA 116 A˚ 2 Metabolism: aromatic O O OH H log P 4.94 hydroxylation (ortho to F), glucuronidation

1/ ∗ Cl t 2 7h V 0.6 TAK-442 F 53%∗ CL 12 ∗monkey O pb – Mwt 480.0 Factor Xa inhibitor, ˚ 2 S N O ur – PSA 115 A antithrombotic O O OH log P 2.77 N NH 33 Amides 171

1/ O t 2 3–4 d V 40 TARANABANT ∗ ∗ N O F 31% CL 6.5 monkey N CN H pb 100% Mwt 516.0 Cannabinoid ˚ 2 F3C ur Negligible PSA 75.0 A antagonist, antiobesity log P 7.13 agent; Metabolism: benzylic Cl hydroxylation (at C3CH)

1/ O t 2 8–12 h V – AFN-1252 F 82% CL – Bacterial fatty acid N pb 99% Mwt 375.4 biosynthesis inhibitor O O N N ur – PSA 74.9 A˚ 2 H log P 0.85

34 Lactams and Imides

N-Unsubstituted imides are acidic (pKa of phthalimide in H2O: 8.30) but not enough to undergo extensive deprotonation under physiological conditions. Lactams are also more reactive than noncyclic amides because the cis conformation of the amide group in a lactam has higher energy than the trans conformer of an amide. Lactams and imides react with nucleophiles signiﬁcantly faster than amides. Most imide-containing drugs are ﬁve- or six-membered cyclic imides (Table 34.1), which are more stable than open-chain imides (Scheme 34.1).

O O O O N N NH N 2 O MeO O N O O N O H H Aniracetam Thalidomide Lenalidomide − − t1/2 0.6 h, F 0.2% t1/2 4 7 h, F high t1/2 3 8 h, F 70% O

NH O N N O O O O N O N HN H H O Glutethimide Ethosuximide Dexrazoxane − t 45 h, F 93% − t1/2 10 12 h, F low 1/2 t1/2 2 4 h

Scheme 34.1 Imides as drugs.

34.1 Pyrazolone Antipyretics

Wilhelm Koenigs and Otto Fischer, working at the University of Munich in the 1870s, believed that the antimalarial/antipyretic quinine had a tetrahydroquinoline substructure [1]. With the aim of discovering new antipyretic drugs, they prepared

MeO O O N N N N N N N N OH H

Kairine Kairoline A Thalline Phenazone Aminopyrine − t1/2 12 h, F 97% t1/2 2 3 h, F high

Scheme 34.2 Older antipyretic agents.

In 1883, Ludwig Knorr, also at the University of Erlangen, attempted to prepare a new tetrahydroisochinoline by treating phenylhydrazine with an acetoacetate. The product turned out to be inactive in Filehnes assay, but he recommended to N-alkylate the compound because N-alkylation had reduced toxicity in kairine and kairoline. The resulting product, phenazone, turned out to be a potent and safe antipyretic. The correct pyrazolone structure was established by Knorr in 1887. This compound was marketed by Hoechst under the trade name antipyrine but was later renamed phenazone. It became the best-selling drug worldwide and even outsold sodium salicylate because it tasted better and did not cause gastric irritation. Phenazone can, however, cause agranulocytosis, a drug-induced, often irreversible depletion of neutrophilic granulocytes, which can be fatal. To improve potency and reduce toxicity, further analogs of phenazone were developed, such as aminopyrine, phenylbutazone, oxyphenbutazone, azapropazone, and sulﬁnpyrazone.

34.2 Five-Membered Lactams as Nootropics

The ﬁrst drugs for the treatment of epileptic seizures, bromide salts, were available as early as 1857. Later, phenobarbital and phenytoin and a number of other, more potent and selective antiepileptics were developed. In the early 1960s, various γ-butyrolactams were prepared as cyclic γ-aminobutyric acid (GABA) analogs and tested in animal models, with the aim of discovering new sedatives. However, the compounds turned out to improve memory in rodents, and piracetam and other, related lactams, are used today to improve memory and cognitive function. In 1992, it was discovered at UCB that alkylated derivatives of piracetam had an anticonvulsant effect in mice, which led to the development of the γ-lactam antiepileptics levetiracetam and brivaracetam [2]. 174 34 Lactams and Imides

References

1. Sneader, W. (1996) Antipyretic analgesics. Drug News Perspect., 9, 61–64. 2. Rogawski, M.A. (2008) Brivaracetam: a rational drug discovery success story. Br. J. Pharmacol., 154, 1555–1557.

Table 34.1 Cyclic ﬁve-membered amides, carbamates, ureas, imides, and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 4h V 0.8 PIDOTIMOD HO C O 2 H F 45% CL 2.7 Immunomodulator N N pb Mwt 244.3 O ur 82% PSA 112 A˚ 2 S log P −2.38

t1/ 0.6 h V 2–4 ANIRACETAM O O 2 F 0.2% CL 141 Nootropic N pb – Mwt 219.2 Metabolites: ur – PSA 46.6 A˚ 2 N-(4-methoxybenzoyl)glycine, MeO log P 1.35 4-methoxybenzoic acid

1/ t 2 18–28 h V – CROMAKALIM O F – CL – Potassium channel opener, N pb – Mwt 286.3 antihypertensive; Metabolism: NC OH ur – PSA 73.6 A˚ 2 glucuronidation, oxidation and log P 1.27 hydrolysis of pyrrolidone to O succinamide

t1/ 4±2h V 0.5–0.7 NEFIRACETAM O 2 H F – CL 1.5–2.2 Nootropic N N pb – Mwt 246.3 Metabolism: hydroxylation of O ur 5% PSA 49.4 A˚ 2 pyrrolidone (mainly at position 5), log P 0.64 then ring ﬁssion

1/ t 2 5–7 h V 2–3 PRAMIRACETAM H O F – CL 4–5 Nootropic N N N pb 30% Mwt 269.4 O ur – PSA 52.7 A˚ 2 log P −1.40

1/ ± . ± . t 2 5 1h V 0 6 0 1 PIRACETAM O F 100% CL – Nootropic H N 2 N pb 0% Mwt 142.2 No metabolism O ur 80–100% PSA 63.4 A˚ 2 log P −1.75 175

1/ O t 2 3–8 h V 1–2 OXIRACETAM F 75±7% CL 1.8 Nootropic H2N N pb – Mwt 158.2 Almost no metabolites O ur 50–84% PSA 83.6 A˚ 2 formed in rats OH log P −2.48

1/ . ± . t 2 6–8 h V 0 6 0 1 LEVETIRACETAM O F 100% CL 0.96 Antiepileptic H N pb <10% Mwt 170.2 Metabolism: hydrolysis of 2 N ur 70% PSA 63.4 A˚ 2 CONH O 2 log P −0.88

1/ ± t 2 8 1h V 0.5 BRIVARACETAM O F 100% CL 0.8 Antiepileptic H N 2 N pb 18% Mwt 212.3 Metabolism: hydrolysis of ˚ 2 O ur 5–9% PSA 63.4 A CONH2 log P 0.88

1/ O t 2 8h V 0.6 SELETRACETAM F >90% CL – Anticonvulsant H2N N pb <10% Mwt 232.2 Metabolism: hydrolysis of O ˚ 2 F ur 30% PSA 63.4 A CONH2 log P 0.71 F

1/ O t 2 3–5 h V – PHENYLPIRACETAM H N F 100% CL – Nootropic 2 N pb – Mwt 218.3 O ur 40% PSA 63.4 A˚ 2 log P 0.70

t1/ 6–8 h V 0.5 ROLIPRAM O 2 F 74% CL 2–6 Antidepressant; Metabolism: pb – Mwt 275.3 O-dealkylation, 2- and HN O ur Low PSA 47.6 A˚ 2 3-hydroxylation of cyclopentyl, log P 2.00 5-hydroxylation of pyrrolidone; PK OMe of both isomers is similar, only R(−) isomer is active

1/ t 2 12–16 h V 0.9 COTININE O F 84–100% CL 0.9 Metabolite of nicotine; Metabolism: N pb – Mwt 176.2 N-methylation and oxidation of H ur 12% PSA 33.2 A˚ 2 pyridine, hydroxylation of N log P 0.08 pyrrolidinone, demethylation, glucuronidation (continued overleaf ) 176 34 Lactams and Imides

1/ HO t 2 4–10 h (iv) V 0.5–1.1 3-HYDROXYCOTININE F – CL 1.1–2.6 Metabolite of cotinine O pb – Mwt 192.2 N ur – PSA 53.4 A˚ 2 H log P −1.12 N

1/ O t 2 0.9–2.5 h V 1.1–1.6 TOLOXATONE F 50–62% CL 8–14 Antidepressant, MAO inhibitor O N pb 51% Mwt 207.2 Metabolism: glucuronidation, 2 ur <1% PSA 49.8 A˚ oxidation of CH3 to CO2H HO log P 1.53

O t1/ 9–16 h V 0.5–0.7 CIMOXATONE O 2 F – CL 0.4–0.8 Antidepressant, MAO inhibitor O N pb 93–96% Mwt 338.4 Active metabolite: O-desmethyl < 2 1/ ur 1% PSA 71.8 A˚ (t 2 36 h) MeO CN log P 2.25

O t1/ 11–22 h V –BEFLOXATONE O 2 F – CL – Antidepressant, MAO inhibitor OH O N pb 58% Mwt 349.3 Active metabolite: O-desmethyl < ˚ 2 1/ CF3 ur 0.2% PSA 68.2 A (t 2 22 h) MeO log P 1.91

1/ O t 2 4–7 h V 0.6–0.9 LINEZOLID N F 80–100% CL 1.6–2.2 Antibacterial O pb 31% Mwt 337.4 Metabolism: oxidative ring ur 30–40% PSA 71.1 A˚ 2 opening of morpholine O O N F log P 0.45 HN

1/ O t 2 7–11 h V 0.8 RIVAROXABAN N F 80–100% CL 2.6 Factor Xa inhibitor, antithrombotic O pb 92–95% Mwt 435.9 Metabolism: oxidative degradation O ˚ 2 Cl S O O N ur 36% PSA 116 A of morpholinone to log P 1.84 N-(2-hydroxyethyl)oxalamide, HN amide hydrolysis 177

1/ . ∗ O t 2 4–27 h V 0 17 APIXABAN ∗ ∗ N F 51% CL 0.8–1.3 chimpanzee pb 87% Mwt 459.5 Anticoagulant, factor O N ur 13% PSA 111 A˚ 2 Xa inhibitor MeO log P 0.56 Metabolism: hydroxylation, O N O-demethylation, then N NH2 O-sulfation O

1/ . ∗ F t 2 9–83 h V 0 31 ANACETRAPIB F 13%∗ CL 0.11∗∗monkey pb >99% Mwt 637.5 Cholesterol ester transfer < ˚ 2 O OMe ur 0.1% PSA 38.8 A protein inhibitor, antilipemic log P 8.81 Metabolism: O-demethylation, O N hydroxylation F3C

CF3

1/ ± / O t 2 9 5h V F 12.3 METAXALONE O F – CL 17 Muscle relaxant pb – Mwt 221.3 Metabolism: oxidation of O N ur 27% PSA 47.6 A˚ 2 CH to CO H, H 3 2 log P 1.18 O-dealkylation to phenol

1/ ± . ± . t 2 14 2h V 0 7 0 1 TRIMETHADIONE O F – CL – Anticonvulsant, teratogenic pb 0% Mwt 143.1 Metabolism: N-demethylation O O N ur <3% PSA 46.6 A˚ 2 to dimethadione log P 0.79

1/ t 2 6–13 d V 0.4–0.5 DIMETHADIONE O F – CL – Metabolite of trimethadione O O pb Low Mwt 129.1 N ˚ 2 H ur – PSA 55.4 A log P 0.77

1/ ± . ± . t 2 45 8h V 0 7 0 2 ETHOSUXIMIDE F 93±2% CL/F 0.19±0.04 Anticonvulsant pb 0% Mwt 141.2 Metabolism: hydroxylation O N O ur 25±15% PSA 46.2 A˚ 2 at ethyl (both carbons) H log P 0.25 and CH2CO (continued overleaf ) 178 34 Lactams and Imides

1/ t 2 7.8 h V – PHENSUXIMIDE F – CL – Anticonvulsant pb 21% Mwt 189.2 Metabolism: N-demethylation, ur Low PSA 37.4 A˚ 2 aromatic 4-hydroxylation O N O log P 0.04

1/ . ± . t 2 2 5 1 5h V – METHSUXIMIDE F – CL – Anticonvulsant; active metabolite: 1/ pb Low Mwt 203.2 N-desmethyl (t 2 2–3 d; pb 50%) O N O ur <1% PSA 37.4 A˚ 2 Further metabolism: aromatic and log P 0.42 methyl hydroxylation

1/ O t 2 40–70 h V 0.8 SORBINIL NH F – CL – Aldose reductase inhibitor HN pb – Mwt 236.2 Metabolites: 2-hydroxy, F O ur 26±7% PSA 67.4 A˚ 2 5-(2-hydroxyethyl)-5-(2-hydroxy- log P 0.49 5-ﬂuorophenyl)- O imidazolidinedione

1/ O t 2 1–2 h V – FIDARESTAT NH F – CL – Aldose reductase inhibitor, HN pb – Mwt 279.2 treatment of diabetic neuropathy F O ur – PSA 111 A˚ 2 log P −0.13 O CONH2

1/ t 2 5–6 h V 0.25 PIOGLITAZONE > γ H O F 80% CL – PPAR- agonist, insulin sensitizer > N pb 99% Mwt 356.4 Metabolism: thiazolidinone NH ˚ 2 S ur Low PSA 93.6 A hydrolysis, benzylic hydroxylation O log P 3.50 of ethyl, then oxidation to ketone O 1/ (t 2 16–23 h); withdrawn in 2011 because of carcinogenicity

1/ t 2 3.6–4.2 h V 0.19 ROSIGLITAZONE F 86–100% CL 0.6 PPAR-γ agonist, insulin O pb 99.7% Mwt 357.4 sensitizer; Metabolism: ur 0% PSA 96.8 A˚ 2 N-demethylation, 3- and NH N N S log P 2.56 5-hydroxylation of pyridine, then O O sulfation and glucuronidation; withdrawn in 2010 in Europe for increasing heart attack risk 179

1/ . ∗ t 2 10–15 h V 0.14–0 17 RIVOGLITAZONE O F 76%∗ CL 0.31–0.37∗∗monkey; PPAR-γ agonist, NH pb – Mwt 397.5 insulin sensitizer S ∗ ˚ 2 N O ur 0.3% PSA 103 A Metabolism (monkey): O- and N O log P 2.95 N-demethylation, thiazoline MeO hydroxylation, thiazoline ring opening

1/ t 2 16–34 h V 2.5 TROGLITAZONE O F 40–50% CL 8.5 PPAR-γ agonist > NH pb 99% Mwt 441.5 Metabolism: O-sulfation, O S 2 O ur 0% PSA 110 A˚ O-glucuronidation, oxidation to O log P 4.69 benzoquinone (chromane ring HO scission); withdrawn in 2000 because of hepatotoxicity

1/ t 2 38–59 h V – NILUTAMIDE F 80–90% CL 2.5∗∗rat O pb 84% Mwt 317.2 Antiandrogen, antineoplastic NO2 ur <2% PSA 95.2 A˚ 2 Metabolism: N log P 3.35 CH3-hydroxylation, reduction of HN CF3 NO to NH , then aromatic O 2 2 hydroxylation (ortho to NH2), reduction of C=OtoCHOH

O t1/ 8–14 h V – BMS-564929 CN 2 HO H F – CL – Selective androgen N pb – Mwt 305.7 receptor modulator Cl N ur – PSA 84.6 A˚ 2 O log P 0.43

1/ ± . ± . t 2 15 9h V 0 64 0 04 PHENYTOIN F 90±3% CL – Anticonvulsant CYP2C9 H pb 89±23% Mwt 252.3 substrate, carcinogen N ur 2±8% PSA 58.2 A˚ 2 Metabolism: aromatic O log P 1.42 4-hydroxylation, then N H O glucuronidation

1/ t 2 8–15 min V 0.07–0.17 FOSPHENYTOIN F Low CL – Prodrug of phenytoin H pb 95–99% Mwt 362.3 N ˚ 2 O ur – PSA 126 A HO O N log P −1.06 P O HO O

(continued overleaf ) 180 34 Lactams and Imides

1/ H t 2 1.9 h (iv) V – MOFEBUTAZONE N > O N F 90% CL – Antiinﬂammatory pb 99% Mwt 232.3 Metabolism: glucuronidation ˚ 2 O ur 8% PSA 49.4 A log P 2.26

1/ ± t 2 56 8h V 0.1 PHENYLBUTAZONE F 90±10% CL 0.02 Antiinﬂammatory pb 96±1% Mwt 308.4 Metabolism: aromatic ur 1% PSA 40.6 A˚ 2 4-hydroxylation N log P 3.38 (to oxyphenbutazone, see below), O N hydroxylation at CH2CH3 O

1/ t 2 27–64 h V 0.15 OXYPHENBUTAZONE F – CL 0.03 Active metabolite of OH pb >98% Mwt 324.4 phenylbutazone; withdrawn in N ur <2% PSA 60.9 A˚ 2 1985 for causing blood dyscrasias O N log P 2.74 O

1/ t 2 22–33 h V 0.3–0.5 FEPRAZONE F – CL 0.1–0.2 Antiinﬂammatory pb 90% Mwt 320.4 Metabolism: hydroxylation of N ur <1% PSA 40.6 A˚ 2 methyl and phenyl groups, O N log P 3.05 C-glucuronidation O

1/ ± . ± . t 2 4 1h V 0 74 0 23 SULFINPYRAZONE F 100% CL 2.4±0.6 Antithrombotic, uricosuric pb 98.3±0.5% Mwt 404.5 Metabolism: oxidation to N ur 39±9% PSA 76.9 A˚ 2 sulfone, reduction to sulﬁde O N O 1/ ± log P 1.89 (t 2 14 5h) S O

1/ t 2 10–24 h V 0.15 AZAPROPAZONE, APAZONE N N F 83±19% CL 0.14 Antiinﬂammatory N pb 99.5% Mwt 300.4 Metabolism: O N ur 63% PSA 56.2 A˚ 2 aromatic hydroxylation log P 1.78 O 181

t1/ 10–17 h V 1 MUZOLIMINE N 2 H2N N F – CL – Diuretic Cl pb 65% Mwt 272.1 Metabolism: hydrolysis of O ur 5% PSA 58.7 A˚ 2 amide, then decarboxylation Cl log P 2.10

1/ t 2 12 h (iv) V 0.77 ANTIPYRINE, PHENAZONE N F 97% CL 0.64 Analgesic N pb 7% Mwt 188.2 Metabolism: hydroxylation of ˚ 2 O ur – PSA 23.6 A vinylic methyl group log P 0.44

1/ t 2 1.0–1.5 h V 1.3–2.0 PROPYPHENAZONE N N F – CL 11 Analgesic, antipyretic pb Low Mwt 230.3 Metabolism: N-demethylation, ˚ 2 O ur 0.6% PSA 23.6 A hydroxylation of iPr log P 1.72 and phenyl

1/ t 2 2.1–3.2 h V 0.7 AMINOPYRINE, AMIDOPYRINE F High CL 2 Analgesic, antipyretic N N pb 15% Mwt 231.3 Metabolism: N-demethylation of 2 ur 3–10% PSA 26.8 A˚ NMe2, then N-acetylation and N O log P 0.85 N-formylation; withdrawn in 1970 because of bone marrow suppression

1/ t 2 2.6–3.5 h V – METAMIZOL, DIPYRONE F 85%∗ CL 2.8 ∗metabolites only pb 58% Mwt 311.4 Analgesic, antipyretic ur 2–4% PSA 84.6 A˚ 2 Metabolites: − . N log P 1 50 4-(methylamino)antipyrine 1/ . N (t 2 3 8h), HO3S 4-(formylamino)antipyrine 1/ N O (t 2 10 h), 4-aminoantipyrine 1/ t 2 4–6 h), 4-(acetylamino)antipyrine 1/ (t 2 11 h); withdrawn in 1977 for causing agranulocytosis

1/ ∗ t 2 4–12 h V 0.5–0.9 CARBIMAZOLE ∗ S O F –CL3.7prodrug of methimazole pb 40% Mwt 186.2 (see below); all values: N N 2 O ur 7% PSA 64.9 A˚ methimazole on oral dosing of log P 0.16 carbimazole; antihyperthyroid; complete absorption (continued overleaf ) 182 34 Lactams and Imides

1/ SH t 2 3–6 h V 0.6–0.9 METHIMAZOLE, THIAMAZOLE F 95% CL 1.4–3.7 Antihyperthyroid N N pb – Mwt 114.2 Metabolite: ur 7% PSA 47.4 A˚ 2 3-methyl-2-thiohydantoin − . 1/ log P 0 34 (t 2 9h)

1/ O t 2 2–3 h (iv) V 0.3–0.4 AVIBACTAM, NXL-104 F – CL 2–3 β-Lactamase inhibitor, O N N NaO S O pb – Mwt 265.2 antibacterial ur – PSA 139 A˚ 2 O O NH2 log P −1.87

1/ O t 2 1–2 h V 1.8 ENOXIMONE F 45–70% CL 6.8–30 Cardiotonic HN NH pb 70–85% Mwt 248.3 Metabolism: reversible MeS ur 0.5% PSA 83.5 A˚ 2 oxidation to sulfoxide log P 3.72 O

1/ O t 2 1.3 h V 0.6–1.7 PIROXIMONE F >80% CL 7–9 Inotropic HN NH pb 85% Mwt 217.2 Metabolism (dog): reduction of N ur 64% PSA 71.1 A˚ 2 ketone to alcohol, oxidative log P 2.15 cleavage to isonicotinic acid O

1/ O NH2 t 2 1.5 h V –NAFTAZONE F High CL – Hemostatic, vasoprotectant NH N pb 0% Mwt 215.2 Metabolism: reduction of ketone ˚ 2 O ur – PSA 84.6 A to alcohol, glucuronidation log P 0.95

1/ t 2 4–5 d V 26 AZIMILIDE N N F 85% CL 2.5 Antiarrhythmic O N pb 94% Mwt 458.0 Metabolism: oxidation to N-oxide, O < ˚ 2 N ur 10% PSA 72.6 A N-demethylation, hydrolysis of Cl N log P 3.33 hydrazone and oxidation of CHO O to CO2H, N-dealkylation and oxidation to butanoic acid 183

H t1/ 9h V 0.54 DANTROLENE O N 2 F 70–88% CL – Muscle relaxant O N pb High Mwt 314.3 Metabolism: reduction of NO2 to O2N N ˚ 2 O ur 1–4% PSA 121 A NH2, then N-acetylation, log P 1.07 hydroxylation of CH2N

H t1/ 1.0±0.2h V 0.58±0.12 NITROFURANTOIN O N 2 F 90±13% CL 9.9±0.9 Antibacterial O N pb 62±2% Mwt 238.2 Metabolism: reduction of NO2 N ± ˚ 2 O ur 47 13% PSA 121 A O2N log P −0.47

1/ O NH2 t 2 5 h (cattle) V – NITROFURAZONE F – CL – Antibacterial NH N pb – Mwt 198.1 Metabolism: reduction of NO2; O ur – PSA 126 A˚ 2 withdrawn in 1974 O2N log P 0.47 because of carcinogenicity

1/ ± O t 2 3 1h V 12 NIFURTIMOX S O F Low CL – Antibacterial N pb – Mwt 287.3 Metabolite: nitrite N < ˚ 2 O ur 1% PSA 117 A O2N log P 0.73

1/ t 2 12–15 h V – NIRIDAZOLE F –CL–Anthelmintic S pb – Mwt 214.2 Metabolism: hydroxylation, O2N N NH ur <1% PSA 119 A˚ 2 oxidation to 4-ketoniridazole, N O log P 0.95 hydrolysis of nitrothiazole to 1- thiocarbamoyl-2-imidazolidinone

1/ ∗ ∗ t 2 6min V 30 NITAZOXANIDE ∗ F High∗ CLF 1.3–2.2∗ tizoxanide on oral administration > ∗ of prodrug S H pb 99% Mwt 307.3 O N N 2 1/ . 2 ur – PSA 142 A˚ Prodrug of tizoxanide (t 2 1 8h); antiprotozoal N O O O log P 2.74 Metabolism: deacetylation to tizoxanide, then glucuronidation

35 Nitriles

The cyano group is strongly electron-withdrawing and may be used to lower the electron density of an arene or heteroarene, to reduce the basicity of amines, or to enhance the polar surface area and solubility of a lead. Nitriles are metabolically quite stable, as shown by the examples in Scheme 35.1 [1].

CN N NC OH N N H N

H NC N N O NC CN Dienogest Anastrozole Letrozole t 8 h, F 90% 1/2 t1/2 41 h t1/2 42–82 h, F 100% H NC N N NH 2 HO O O O H N F3C N S N NC Br O O NC F Bicalutamide Citalopram NC t1/2 2–16 d F t1/2 35–43 h Etravirine F 100% t1/2 30–40 h

Scheme 35.1 Therapeutic nitriles.

The N-cyanoguanidine group has been used as nontoxic thiourea bioisostere in cimetidine. The potassium channel opener pinacidil also contains a cyanoguanidine substructure. In principle, nitriles may be hydrolyzed in vivo to amides or carboxylic acids, but such metabolites are rarely observed. Interestingly, simple nitriles such as RCH2CN or R2CHCN (R = alkyl; not tert-butyl cyanide) undergo displacement and release of cyanide in rats [2]. If this metabolic transformation also occurs in humans, this would be a problem only in compounds that must be dosed in large quantities. Small amounts of cyanide are goitrogenic (cyanide is metabolized

References

1. Fleming, F.F., Yao, L., Ravikumar, P.C., Funk, L., and Shook, B.C. (2010) Nitrile-containing pharmaceuticals: efﬁcacious roles of the nitrile pharmacophore. J. Med. Chem., 53, 7902–7917. 2. (a) Silver, E.H., Kuttab, S.H., Hasan, T., and Hassan, M. (1982) Structural considerations in the metabolism of nitriles to cyanide in vivo. Drug Metabol. Dispos., 10, 495–498; (b) Dahl, A.R. and Waruszewski, B.A. (1989) Metabolism of organonitriles to cyanide by rat nasal tissue enzymes. Xenobiotica, 19, 1201–1205. 186

36 Carbonates

Carbonates have often been used as prodrugs, but rarely as a structural element of drugs. Carbonates are chemically more stable than esters, but this seems not to be the case in vivo. One problem may be that effective steric shielding of the carbonyl group in carbonates is more difﬁcult than in esters. Examples of typical carbonate-based prodrugs for carboxylic acids or phenols are sketched in Scheme 36.1.

O O O O S S N N H H CO N N in vivo N N 2 + CH3CHO O O O O OH O EtOH

O Piroxicam Ampiroxicam antiinflammatory prodrug of piroxicam, t1/2 48 h, F high less irritant than parent, not detectable in plasma MeO OMe N N H H O N S N O N N N O O O H N O O O N NH 2 O N O O S O O O HO OH OMe O O O O OH

Candesartan cilexetil Cefpodoxime proxetil Sergliflozin etabonate

O O OH H2N O O N O N H H O N S N S N N N O O N S N NH O O O O O O Cefcanel daloxate Olmesartan medoxomil

Scheme 36.1 Carbonate prodrugs.

37 Carbamates

The resistance of carbamates toward nucleophilic attack lies between that of carboxylic esters and amides. Carbamates of primary amines (RNHCO2R ) can also fragment into isocyanates and alcohols on treatment with bases, a further potential pathway of metabolic degradation. Short-lived carbamates have been used as prodrugs of heteroaromatic amines (capecitabine), amidines (lefradaﬁban, dabigatran), and phenols (bambuterol). Examples of such compounds and other short-lived carbamates, in which carbamate hydrolysis is the main metabolic pathway, are shown in Scheme 37.1.

H O O N N O

N O HN O F H MeO N O OH O HO Capecitabine O NH Lefradafiban OMe − t1/2 0.5 0.9 h, F 100% t1/2 12 h, F 24% prodrug of 5-fluorouracil prodrug of fradafiban (amidine/acid), not detectable in plasma all values: fradafiban on prodrug administration, po N O O H H OEt N N N OEt H N HO N N O N O N N O

Tiracizine Cadralazine Neostigmine − − t1/2 2.4 h, F 34% t1/2 1 3 h, F >80% t1/2 1.3 h, F 1 2%

Scheme 37.1 Carbamates as prodrugs or short-acting drugs. Sterically undemanding carbamates derived from nonbasic amines (anilines, heteroarylamines), hydrazines, and amidines are less stable than those derived from ammonia or aliphatic amines. The latter can be sufﬁciently long lived to serve as oral drugs, as illustrated by the examples in Scheme 37.2. Cyclic ﬁve- or six- membered carbamates are quite stable and do not usually undergo metabolic ring opening. In the examples in Scheme 37.2, carbamate hydrolysis is not necessarily the half-life-determining metabolic reaction.

CO2H O O OMe N N N O N O O O Rivastigmine Muraglitazar − − − t1/2 1 2 h, F 35 72% t1/2 19 27 h, F 79%

CO Me O N O 2 O O N NH2 NH HN H H O O N H2N N Roxifiban Entinostat O NH t1/2 5 d (acid) t1/2 52 h F 21% (acid on oral dose of ester) F 85% O OEt O O NH MeO N S HN N N N NH2 H H Albendazole sulfoxide F Flupirtine − t1/2 8 12 h t1/2 8.5 h main active metabolite of albendazole F 90%

O O H N F3C H N O O NH O Cl 2 2 O O N Ph N O H

Felbamate Fenspiride Efavirenz − − t1/2 21 h, F 90% t1/2 15 h, F 9% t1/2 40 55 h, F 40 45%

Scheme 37.2 Therapeutic carbamates.

37.1 Carbamates as Hypnotics

The first substances known to induce sleep were bromide and ethanol. In 1869, Oscar Liebreich discovered the hypnotic properties of chloral (trichloroacetaldehyde) that became widely used for this purpose. Because of the foul taste and irritating effect on the stomach, alternatives were sought, and Josef von Mering and Oswald Schmiedeberg at the University of Strasbourg discovered ethyl carbamate (urethane) as a weak, nonirritating hypnotic. The hypothesis behind their discovery was that urethane would be decomposed in the body to ethanol and the respiratory stimulants carbon dioxide and ammonia, what should provide for a safe hypnotic. It turned out, however, that intact ethyl carbamate was the hypnotic agent. Further structural variations and combinations of low-molecular-weight alcohols, aldehydes, carbamates, ureas, and cyclic imides led to increasingly potent References 189 hypnotics and anticonvulsants, such as the acylureas, barbiturates, glutarimides, succinimides, hydantoins, and quinazolones (Tables 34.1, 37.1, and 38.1) [1]. A particularly tragic event was the launch of racemic thalidomide (Contergan) as sedative by the German company Grunenthal¨ in 1957. Hardly any clinical trials had been performed before commercialization. Thalidomide causes peripheral neuritis, and it is also strongly teratogenic. Until its withdrawal in 1961, more than 1000 babies with horrible malformations, typically shortened or absent long bones of arms and legs (phocomelia), were born in Germany and Australia. The thalidomide disaster shattered confidence in the pharmaceutical industry and led to much stricter regulations and to a significant improvement of the quality of new drugs [2].

References

1. (a) Sneader, W. (1997) Anticonvulsants. Drug News Perspect., 10, 156–160; (b) Sneader, W. (1993) Hypnotics. Drug News Perspect., 6, 182–186. 2. Botting, J. (2002) The history of thalidomide. Drug News Perspect., 15, 604–611.

Table 37.1 Noncyclic carbamates. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 10–11 h V 0.75 MEPROBAMATE F – CL 2–3 Anxiolytic H2N O O NH2 pb 15% Mwt 218.3 Metabolism: hydroxylation to ur 8–20% PSA 105 A˚ 2 2-hydroxypropyl metabolite O O log P 0.70

1/ t 2 8h V – CARISOPRODOL H F – CL – Muscle relaxant N O O NH2 pb 58% Mwt 260.3 Metabolism: hydroxylation, ur <1% PSA 90.7 A˚ 2 N-deisopropylation to O O log P 2.10 meprobamate

1/ t 2 3h V – TYBAMATE H F – CL – Anxiolytic N O O NH2 pb 77% Mwt 274.4 Metabolism (rat, dog): ur – PSA 90.7 A˚ 2 propyl 2-hydroxylation, O O log P 2.76 N-debutylation

1/ ± / . ± . t 2 21 2h V F 0 76 0 08 FELBAMATE F >90% CL/F 0.50±0.13 Anticonvulsant; Metabolism: pb 22–25% Mwt 238.2 aromatic 4-hydroxylation, ur 45±5% PSA 105 A˚ 2 hydrolysis of carbamoyl, then H N O O NH 2 2 log P 0.73 oxidation to aldehyde, then O O elimination to α,β-unsaturated aldehyde; hepatotoxic

(continued overleaf) 190 37 Carbamates

t1/ 0.9–2.0 h V – METHOCARBAMOL OMe OH 2 F 32% CL 3–13 Muscle relaxant O O NH 2 pb 46–50% Mwt 241.2 Metabolism: O-demethylation, ˚ 2 O ur 10–15% PSA 91.0 A aromatic hydroxylation log P 0.40

1/ t 2 5–8 h V – PHENPROBAMATE F – CL – Anxiolytic, muscle relaxant O NH2 pb 81% Mwt 179.2 Metabolism: aromatic ur 7% PSA 52.3 A˚ 2 hydroxylation, oxidative O log P 1.93 degradation of carbamate

1/ t 2 10–14 h V 1 CARISBAMATE Cl OH F 94% CL 0.7–1.0 Antiepileptic O NH2 pb <60% Mwt 215.6 Metabolism: glucuronidation < ˚ 2 O ur 5% PSA 72.6 A log P 1.38

t1/ 2–3 h V 4.5 CAPRAVIRINE Cl N 2 F Good CL – Antiviral (discontinued) pb – Mwt 451.4 Metabolites: pyridine-N-oxide, S ur Negligible PSA 108 A˚ 2 sulfoxide, sulfone Cl log P 4.20 N N O NH2 O

1/ . ± . . ± . t 2 1 3 0 8h V 0 7 0 3 NEOSTIGMINE F 10–20% CL 8.4±2.7 Cholinergic, miotic, antidote N O N pb Negligible Mwt 223.3 for neuromuscular blocking 2 O ur 67% PSA 29.5 A˚ agents (e.g., curare); Metabolism: log P −2.34 hydrolysis of carbamate

1/ t 2 1–2 h V 0.7–3.2 RIVASTIGMINE F 35–72% CL 5.2–20 Nootropic, crosses bbb O N N pb 40% Mwt 250.3 Metabolism: hydrolysis of O ur 0% PSA 32.8 A˚ 2 carbamate, N-demethylation log P 2.14

1/ t 2 0.5 h V 1–2 PHYSOSTIGMINE H ∗ ∗ O N F 3% CL 22–190 36% (transdermal) N pb 30–40% Mwt 275.4 Cholinergic, miotic, O 2 H N ur <4% PSA 44.8 A˚ crosses bbb log P 1.27 191

t1/ 12 h V 1.1 EPTASTIGMINE H 2 O N F –CL12Cholinergic N pb – Mwt 359.5 O 2 H N ur – PSA 44.8 A˚ log P 4.41

1/ . ∗ O O t 2 211 h V 1.1–2 5 TORCETRAPIB F 33–45%∗ CL 6–12∗∗rat, monkey N pb – Mwt 600.5 CETP inhibitor for treatment of CF 3 ur 0% PSA 59.1 A˚ 2 atherosclerosis; development

F3C log P 8.16 discontinued MeO N CF3 O

38 Ureas

Acyclic ureas are similarly stable as amides toward enzymatic hydrolysis but have been used less frequently in drug design. Illustrative examples are shown in Scheme 38.1. The most important drugs with a urea substructure are N-nitroso-N- (2-chloroethyl)ureas (Chapter 12), N-sulfonylureas (Chapter 64), and barbiturates.

O O O O O N N N O N OH N NH2 H2N N N H H N N O O H O N-Hydroxyurea Diethylcarbamazine Morocromen Naftazone t 3–6 h 1/2 t1/2 5–13 h t1/2 3–4 h t1/2 1.5 h F 100% F > 90% F 67–79% F high O O

N HN N

N N Lisuride CF3 t1/2 1.5–2.0 h H O N F 20% O F N HN F CF N N F O N 3 H N Casopitant N Telcagepant t 9–15 h N t 5–8 h 1/2 CF O 1/2 F 34% (dog) 3 H F 35% (dog)

O O

N NH in vivo N NH2 O 2 H + S OH S S O Zileuton t1/2 2–4 h

Scheme 38.1 Therapeutic ureas.

The parent, unsubstituted urea is used as osmotic diuretic. It must be dosed intravenously because its oral bioavailability is too low. The antineoplastic hydroxyurea, however, is readily absorbed from the gastrointestinal tract and even crosses the blood–brain barrier (bbb). N-Hydroxyureas may undergo metabolic N−O bond cleavage, as shown below for the antiasthmatic zileuton. Among the ﬁrst hypnotics were N-acylureas such as carbromal, bromisovalum, and pheneturide (Scheme 38.2), but no complete pharmacokinetics (PK) proﬁle was determined for these drugs. Noncyclic acylureas are less potent than barbiturates, and are no longer used as hypnotics.

Br Br O O H2N

H2N N O H2N N O O N O H H H

Carbromal Bromisovalum Pheneturide t1/2 7–15 h t1/2 13 h t1/2 60 h

Scheme 38.2 Older hypnotic ureas.

After discovering the weak hypnotic ethylcarbamate, Josef von Mering, working at the University of Strasbourg, continued to prepare carbamates and ureas with the aim of ﬁnding better hypnotics. After discovering the potent hypnotic N-(2- ethylbutanoyl)urea, he decided to prepare cyclic N-acylureas. One of these was 5,5-diethylbarbituric acid (barbital). Because he had doubts about the real structure of his product, he asked his friend Emil Fischer for help. Fischer together with his nephew Alfred Dilthey resynthesized the compound, and it turned out to be the most potent hypnotic ever seen. It was marketed by Bayer as Veronal in 1903 [1]. Hypnotics such as ethanol and barbiturates act by suppressing polysynaptic responses in the central nervous system (CNS), by interacting with various γ- aminobutyric acid (GABA) receptors, and by inhibiting glutamate-activated ion currents, without binding speciﬁcally to any receptor. Interestingly, despite their large polar surface area (PSA), barbiturates and related hypnotics are able to cross the bbb and enter the CNS. Barbiturates are more potent and show fewer side effects than the older hypnotics chloral, paraldehyde, sulfonal, or the simple aliphatic carbamates hedonal or ethyl carbamate. Barbiturates were extensively used for many years as sedatives, hypnotics, anticonvulsants, and anesthetics (Table 38.1). From the 1960s, however, barbiturates have been largely displaced by benzodiazepines, which have a higher therapeutic index and a lower liability for drug–drug interactions, tolerance, and abuse.

Reference

1. Sneader, W. (1993) Hypnotics. Drug News Perspect., 6, 182–186. 194 38 Ureas

Table 38.1 Thioamides, thioureas, and six-membered lactams, imides, and ureas (barbiturates). V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 1h V 0.7 ELESCLOMOL S S H H F – CL 13 Apoptosis inducer, inducer of N N N N pb – Mwt 400.5 oxidative stress, HSP70 2 O O ur – PSA 129 A˚ inducer, oncolytic log P 1.98

1/ t 2 60–120 h V –DISULFIRAM F >80% CL 9–12 Aldehyde dehydrogenase S pb 96% Mwt 296.5 inhibitor for treatment of 2 S N ur – PSA 121 A˚ alcoholism; crosses bbb; N S log P 3.82 CYP2E1 inhibitor, hepatotoxic S Active metabolite: diethylthiomethylcarbamate (Et2NCO(SCH3))

1/ H t 2 3h V –AMOCARZINE N F <40% CL – Anthelmintic S pb – Mwt 371.5 Metabolism: N-oxidation 2 O2N N N ˚ H ur 1.5% PSA 108 A N log P 2.32

1/ t 2 5–13 h V 1.7–5.7 DIETHYLCARBAMAZINE O F >90% CL – Anthelmintic N N pb Negligible Mwt 199.3 Metabolite: N-oxide . 2 N ur 50% PSA 26 8A˚ log P 1.66

1/ t 2 3–6 h V 0.52 HYDROXYUREA O F 100% CL 1.5 Antineoplastic, crosses bbb OH pb 0% Mwt 76.1 H2N N 2 H ur 80% PSA 75.3 A˚ log P −1.80

1/ O t 2 1.8–3.9 h V 0.9–2.7 ZILEUTON F – CL 7.8–9.6 Antiasthmatic, S H2N N pb 94% Mwt 236.3 antiinﬂammatory, 2 OH ur Negligible PSA 94.8 A˚ 5-lipoxygenase inhibitor log P 3.74

1/ F t 2 15–18 h V 70–79 ABT-761 O F High CL – 5-Lipoxygenase inhibitor H N N pb 99% Mwt 318.4 Metabolism: benzylic 2 2 OH S ur <0.05% PSA 94.8 A˚ hydroxylation, reductive log P 4.56 cleavage of N–O bond 195

1/ ∗ t 2 1–7 min V – FLESTOLOL F ∗∗ F – CL 154–260 iv O H OH N O pb – Mwt 327.4 β-Adrenoceptor antagonist H N N 2 ˚ 2 H O ur – PSA 114 A Metabolism: ester hydrolysis log P 0.91

1/ O t 2 25 h V – LIRIMILAST F – CL – PDE4 inhibitor H2N NH O Cl pb – Mwt 443.3 2 ur – PSA 137 A˚ log P 2.93 O O O Cl S O

1/ t 2 7–15 h V – CARBROMAL Br O F – CL 0.15 Sedative, hypnotic pb 40% Mwt 237.1 Metabolism: hydrolysis of urea H N N O . ˚ 2 2 H ur – PSA 72 2 A to 2-bromo-2-ethylbutyramide, log P 1.62 reductive debromination

1/ t 2 13 h V –BROMISOVALUM Br F –CL0.14(R)∗∗S: 0.012; Sedative, hypnotic O pb – Mwt 223.1 Metabolism: reductive . ˚ 2 H2N N O ur – PSA 72 2 A debromination, S-alkylation of H log P 1.06 cysteine and of N-acetylcysteine

1/ t 2 22–25 h V – PHENACEMIDE F – CL – Antiepileptic

NH2 pb 24% Mwt 178.2 Metabolism: aromatic 2 ur Low PSA 72.2 A˚ 4-hydroxylation O N O H log P 0.87

1/ ± t 2 60 30 h V 3.3 PHENETURIDE F –CL0.68±0.24 Anticonvulsant pb – Mwt 206.2 Metabolism: aromatic H2N 2 ur Low PSA 72.2 A˚ 4-hydroxylation, hydrolysis of O N O H log P 1.73 ureide to 2-phenylbutyric acid

1/ t 2 4.1–7.3 h V 1 THALIDOMIDE O F High CL 2.4 (R)∗∗ ∗S: 66%; ∗∗S:5.0 pb 55% (R)∗ Mwt 258.2 Sedative; Metabolism: N 2 ur <1% PSA 83.6 A˚ hydrolysis of both imides, O log P 0.33 aromatic 4-hydroxylation, O N O H hydroxylation of CH2CO

(continued overleaf ) 196 38 Ureas

1/ t 2 8h V – POMALIDOMIDE O F – CL – Immunomodulator pb – Mwt 273.2 N NH 2 2 ur – PSA 110 A˚ O log P −0.71 O N O H

1/ t 2 3–8 h V 1.2 LENALIDOMIDE O F 70% CL 4.6 Antineoplastic pb 19–29% Mwt 259.3 Metabolism: N-acetylation, N NH 2 2 ur 65% PSA 92.5 A˚ hydrolysis log P −1.09 O N O H

1/ t 2 2–4 h V 0.6–1.1 DEXRAZOXANE O F – CL 3.1–4.8 Cardioprotectant (racemate: N pb <2% Mwt 268.3 antineoplastic) N NH 2 ur 46% PSA 98.8 A˚ Metabolism: hydrolysis O log P −0.91 of imide O N O H

1/ t 2 10–12 h V 2.7 GLUTETHIMIDE F – CL 2.3 Sedative, hypnotic pb 50% Mwt 217.3 Metabolites: glucuronides, < . ˚ 2 O N O ur 2% PSA 46 2 A 4-hydroxyphenyl, 4-hydroxy, H log P 1.75 1-hydroxyethyl

1/ ± t 2 13 2h V 0.8–1.1 AMINOGLUTETHIMIDE F >95% CL 0.8–1.0 Anticonvulsant, inhibitor of pb 20–25% Mwt 232.3 cortisol biosynthesis NH 2 2 ur 35–50% PSA 72.2 A˚ Metabolism: acetylation and O N O log P 0.54 hydroxylation of NH2, H hydroxylation of CH2CO, 1-hydroxylation of ethyl

1/ ± . ± . O t 2 16 3h V 0 7 0 1 ETHYLPHENYLMALONAMIDE F 91±4% CL 0.5±0.1 Metabolite of primidone ± H2N pb 8 1% Mwt 206.2 (see below) 2 ur 79±5% PSA 86.2 A˚ H N O 2 log P 0.35 197

1/ ± . ± . O t 2 15 4h V 0 7 0 2PRIMIDONE F 92±18% CL 0.55±0.12 Anticonvulsant HN pb 19% Mwt 218.3 Metabolites: phenobarbital, 2 ur 46±16% PSA 58.2 A˚ ethylphenylmalonamide N O H log P 0.83

1/ ± . ± . t 2 99 18 h V 0 54 0 03 PHENOBARBITAL O F 100±11% CL 0.06±0.01 Anticonvulsant, sedative, ± HN pb 51 3% Mwt 232.2 hypnotic; Metabolism: 2 ur 24±5% PSA 75.3 A˚ N-glucosylation, O N O H log P 0.53 N-glucuronidation, aromatic 4-hydroxylation

t1/ 30–50 h V – MEPHOBARBITAL O 2 F 75% CL – Anticonvulsant, sedative, N pb 65% Mwt 246.3 hypnotic, CYP inducer 2 ur – PSA 66.5 A˚ Metabolism: aromatic O N O H log P 1.23 4-hydroxylation, N-demethylation

t1/ 25 h V – BUCOLOME O 2 F 100% CL – Antiinﬂammatory, CYP2C9 N pb 90% Mwt 266.3 inhibitor 2 ur – PSA 66.5 A˚ Metabolism: N-glucuronidation O N O H log P 3.61

t1/ 4±1h V 1.2±0.3 HEXOBARBITAL O 2 F >90% CL 3.9±0.7 Sedative, hypnotic N pb 47±5% Mwt 236.3 Metabolism: 2 ur <1% PSA 66.5 A˚ 3-(allylic)-hydroxylation, O N O H log P 1.46 then oxidation to 3 -ketone, little N-demethylation

1/ ± O t 2 13 5h V 0.5–0.7 CYCLOBARBITAL F – CL 0.5–0.6 Sedative, hypnotic HN pb 70% Mwt 236.3 < . ˚ 2 O N O ur 5% PSA 75 3 A H log P 1.50

1/ ± O t 2 8 3h V – HEPTABARBITAL F – CL – Sedative, hypnotic HN pb – Mwt 250.3 Metabolism: dehydrogenation < . ˚ 2 O N O ur 1% PSA 75 3 A to cycloheptadiene H log P 2.03

(continued overleaf ) 198 38 Ureas

1/ ± . ± . O t 2 4 2h V 2 2 0 7 METHOHEXITAL F –CL11±3 Anesthetic N pb 73% Mwt 262.3 Metabolism: 4-(propargylic)- 2 ur <1% PSA 66.5 A˚ hydroxylation O N O H log P 2.01 (no N-demethylation)

1/ ± O t 2 24 10 h V – APROBARBITAL F – CL – Sedative, hypnotic HN pb – Mwt 210.2 Metabolism: epoxidation . ˚ 2 O N O ur – PSA 75 3 A H log P 1.28

t1/ 35–88 h V – BUTALBITAL O 2 F – CL – Sedative, hypnotic HN pb – Mwt 224.3 Metabolism (dog): 2 ur – PSA 75.3 A˚ dihydroxylation of O N O H log P 1.79 alkene, terminal hydroxylation of isobutyl

1/ O t 2 15 h V – TALBUTAL F – CL – Sedative, hypnotic HN pb – Mwt 224.3 Metabolism: dihydroxylation . ˚ 2 O N O ur – PSA 75 3 A of alkene H log P 1.79

1/ O t 2 19–34 h V 1.5 SECOBARBITAL F 90% CL 0.86 Sedative, hypnotic HN pb 50–70% Mwt 238.3 Metabolism: dihydroxylation of . ˚ 2 O N O ur 10–20% PSA 75 3 A alkene, hydroxylation H log P 2.30 at CH2CH3

1/ O t 2 15–40 h V 0.9–1.4 AMOBARBITAL F CL 0.5 Sedative, hypnotic HN pb 50±10% Mwt 226.3 Metabolism: 3-hydroxylation . ˚ 2 O N O ur 1% PSA 75 3 A (at tertiary CH), N-glucosylation H log P 2.18

1/ O t 2 35–50 h V 0.5–1.0 PENTOBARBITAL F – CL 0.50–0.65 Sedative, hypnotic HN pb 50–65% Mwt 226.3 Metabolites: < . ˚ 2 O N O ur 1% PSA 75 3 A 1-methyl-3-hydroxybutyl, H log P 2.18 1-methyl-3-carboxypropyl 199

t1/ 9.0±1.6h V 2.3±0.5 THIOPENTAL O 2 F –CL3.9±1.2 Anesthetic HN pb 85±4% Mwt 242.3 Metabolites: 2 ur <1% PSA 90.3 A˚ 1-methyl-3-hydroxybutyl, S N O H log P 3.05 1-methyl-3-carboxypropyl, pentobarbital

1/ O t 2 18–34 h V – VINYLBITAL F – CL – Sedative, hypnotic HN pb – Mwt 224.3 Metabolism: devinylation . ˚ 2 O N O ur 1.6% PSA 75 3 A (via diol) H log P 1.18

1/ O t 2 34–42 h V 0.8 BUTETHAL F – CL 0.23 Sedative, hypnotic HN pb 26% Mwt 212.3 Metabolism: hydroxylation . ˚ 2 O N O ur 5–9% PSA 75 3 A at CH2CH2CH3 H log P 1.82

t1/ 35–50 h V – BUTABARBITAL O 2 F –CL–∗dog HN pb – Mwt 212.3 Sedative, hypnotic 2 ur 3–5%∗ PSA 75.3 A˚ Metabolism (dog): oxidative O N O H log P 1.67 degradation of 2-butyl to 1-carboxy-2-propyl

1/ O t 2 70 h V – BARBITAL F – CL – Sedative, hypnotic HN pb – Mwt 184.2 Metabolite of N-ethyl- and . ˚ 2 , O N O ur 80% PSA 75 3 A N N -dimethylbarbital H log P 0.80

1/ O t 2 3–6 h V – METHYPRYLON F – CL – Sedative, hypnotic pb – Mwt 183.3 Metabolism: dehydrogenation . ˚ 2 N O ur – PSA 46 2 A to 1,2,3,4-tetrahydropyridine H log P 0.65

1/ ± t 2 41 4h V – CHLORMEZANONE Cl F – CL – Anxiolytic pb 48% Mwt 273.7 Metabolism: amide hydrolysis, 2 O N ur 3% PSA 62.8 A˚ oxidation and conjugation to S O log P 0.48 4-chlorobenzoylglycine; O withdrawn in 1996 for causing epidermal necrolysis

(continued overleaf ) 200 38 Ureas

1/ t 2 40–55 h V 4 EFAVIRENZ F 40–45% CL 2.4 Antiviral (HIV) pb >99% Mwt 315.7 Metabolism: hydroxylation F3C < . 2 Cl ur 1% PSA 38 8 A˚ at arene (position 8, ortho O log P 4.84 of NH) and at tertiary cyclopropyl CH (propargylic O N H position)

1/ t 2 1.1 h V 13.7 CHLORZOXAZONE F 100% CL – Muscle relaxant pb – Mwt 169.6 Metabolism: aromatic H 2 N Cl ur – PSA 38.3 A˚ 6-hydroxylation, then O log P 1.82 hydrolysis of carbamate and O N-acetylation, reductive dechlorination of 6-hydroxychlorzoxazone

1/ H t 2 37 h (iv) V 10 MAXIPOST, BMS 204352 N CF3 F 55% (rat) CL 15 Potassium channel opener O pb >99% Mwt 359.7 Metabolism: demethylation, 2 F ur – PSA 38.3 A˚ then ﬂuoride displacement by log P 2.97 nucleophiles MeO Cl

39 Thiocarbonyl Compounds

Despite their high chemical reactivity and frequent toxicity, a surprisingly large number of drugs contain thiocarbonyl groups. These include tuberculostatics (ethionamide, prothionamide), hypnotics (quazepam), anthelmintics (amocarzine), antihyperthyroids (carbimazole, propylthiouracil), anesthetics (thiopental, methitural), and aldose reductase inhibitors for the prevention of eye and nerve damage in diabetics (epalrestat, tolrestat) (Scheme 39.1).

F3C S S H N N NH2 S N Cl N O N N N 2 H N Ethionamide Quazepam F Amocarzine t1/2 1.9 h t1/2 14–36 h t1/2 3 h F 100% F 29–35% F < 40%

S S H O S O N CO H HN NH N 2 N N N O N N NH S O H 2 Propylthiouracil Thioguanine S Carbimazole Epalrestat t 1–2 h t 0.5–4.0 h t 4–12 h 1/2 1/2 t 1.1 h 1/2 F 75% F 14–46% 1/2

Scheme 39.1 Thiocarbonyl compounds as drugs.

Thiocarbonyl compounds are readily oxidized and then hydrolyzed to the corresponding carbonyl compounds (Scheme 39.2). Thiocarbonyl groups also absorb UV light at longer wavelengths than similar carbonyl compounds (e.g., acetamide: λmax < 210 nm; thioacetamide: λmax = 358 nm) and are often light sensitive. Further metabolic transformations of thiocarbonyl compounds include S-methylation and the reduction of CSNH2 to hydroxymethyl.

O O in vivo HN HN

S N O O N O H H Thiopental Pentobarbital t1/2 9 h t1/2 30–50 h

S in vivo in vivo N S N SH N S S N S S O Disulfiram t1/2 60–120 h, F > 80%

Scheme 39.2 Metabolism of thiocarbonyl compounds.

Oxidized thiocarbonyl derivatives are reactive, potentially toxic electrophiles. One example is metiamide, a potent and orally available histamine H2-antagonist (for suppression of gastric acid formation, Scheme 20.3). Metiamide was developed from burimamide, which had low oral bioavailability because of its high basicity and hydrophilicity. Metiamide, however, was too toxic, and the ﬁnal drug resulting from this program was cimetidine in which the thiourea had been replaced by a less reactive cyanoguanidine group. 203

40 Sulfonic Acids

Sulfonic acids are strong acids (pKa −2), completely deprotonated at physiological pH. Only sulfonic acids of low molecular weight can be absorbed from the intestine and are orally bioavailable. On the other hand, sulfonic acids are highly water soluble and well suited for liquid, parenteral formulations. A selection of therapeutic sulfonic acids is shown in Scheme 40.1 and Table 40.1.

H HO SO H HO S SO HSON H 3 3 3 3 SO H HS 3 O OH Eprodisate Acamprosate Etamsylate Mesna t 16–26 h t 13–18 h t 0.4–8 h 1/2 1/2 t1/2 8 h 1/2 F 44–77% (dog) F 11% F medium F 45–79%

OH N N H H N S N N Cefonicid SO H O N S 3 t1/2 4.4 h O CO2H

Scheme 40.1 Sulfonic acids as drugs.

α-Aminosulfonic acids are unstable and readily decompose into sulfite, aldehydes, and amines, like the bisulfite adducts of aldehydes (α-hydroxysulfonic acids). Accordingly, the solubility of amino-group-containing drugs may be enhanced by converting them into aminosulfonic acid salts (by treatment with formaldehyde and sulfite). This strategy has, for instance, been realized in dipyrone (Scheme 40.2).

O O N in vivo N NH N SO3H N N

Dipyrone 4-(Methylamino)antipyrine t1/2 2.6 h t1/2 3.8 h

Scheme 40.2 Metabolism of dipyrone.

A comparison of PK (pharmacokinetic) data of various analogs of benzylpenicillin is given in Scheme 40.3. The amino group leads to higher oral bioavailability, while the corresponding carboxylic and sulfonic acids show poor oral bioavailability but are better suited for liquid formulations for parenteral administration.

O OH O OH O S H H H H N S N S O N O N O O CO H CO H Sulbenicillin 2 Carbenicillin 2 t1/2 1.2 h (iv) t1/2 1.0–1.5 h F low F 30–40%

NH 2 H H H H N S N S O N O N O O CO2H CO2H Ampicillin Benzylpenicillin t1/2 1.3 h t1/2 30–40 min F 62% F < 30%

Scheme 40.3 Impact of various functional groups on the PK properties of penicillins.

− Table 40.1 Sulfonic acids. V inlkg−1;CLinmlmin−1 kg 1; Mwt in g mol−1.

1/ t 2 13–18 h V 1.1 ACAMPROSATE F 11% CL 3.4–5.7 GABA agonist for treatment of H O O pb Negligible Mwt 181.2 alcoholism; Metabolism: N S 2 OH ur 50% PSA 91.9 A˚ N-deacetylation to homotaurine O log P −2.63 (tramiprosate, an antiamyloidogenic agent for treatment of Alzheimer’s 1/ disease; t 2 2–4 h)

1/ t 2 16–26 h V Small EPRODISATE ∗ ∗ O O O O F 44–77% CL – dog S S pb 0% Mwt 204.2 Treatment of amyloidosis HO OH 2 ur 6.5% PSA 126 A˚ log P −4.10 40 Sulfonic Acids 205

t1/ 8h V 0.4∗ ETAMSYLATE O O 2 F Medium CL 3.5∗∗calves, iv HO S OH pb 95% Mwt 190.2 Hemostatic 2 ur 72% PSA 94.8 A˚ OH log P −1.84

1/ t 2 0.4–8 h V 2.1 MESNA O O F 45–79% CL 12.6 Scavenger of acrolein formed by S pb – Mwt 142.2 metabolism of cyclophosphamide and HS OH 2 ur 36% PSA 54.4 A˚ ifosphamide; Metabolism: log P −2.28 oxidative dimerization to disulﬁde

1/ ∗ t 2 8h V –CYCLAMATE O O F <37% CL – ∗rat, dog S pb – Mwt 179.2 Artiﬁcial sweetener N OH 2 H ur 30–40% PSA 74.8 A˚ Metabolite: cyclohexylamine log P 1.03

1/ OH t 2 18 h V – SULTOSILIC ACID O O F >60% CL 0.8 Antihyperlipidemic S pb – Mwt 344.4 Metabolism: hydroxylation and O SO3H 2 ur 28% PSA 135 A˚ oxidation of methyl log P 0.75

41 Sulfonic Esters

Alkyl sulfonates are strong alkylating agents, similar to alkyl chlorides or bromides, and are usually too reactive to act as reversible ligands of proteins. However, alkylating agents, in particular cross-linking agents, may be useful for the treatment of certain types of cancer. Thus, busulfan, the dimesylate of 1,4-butanediol, is a valuable drug for the treatment of chronic granulocytic leukemia (Scheme 41.1).

O S OH O O O O O O CO2H S O S O S O SO H O 3 O O O Busulfan Sultosilic acid Tesaglitazar t1/2 2.6 h, oral dosing t1/2 18 h, F > 60% t1/2 45 h, F 100%

Scheme 41.1 Sulfonic esters as drugs.

Neopentylic or aryl sulfonates, on the other hand, cannot readily undergo nucleophilic substitution and may, therefore, be used as structural element of nonalkylating drugs.

42 Sulfates and Sulfamic Acids

The O-sulfation of phenols is a typical metabolic transformation to enhance the solubility of xenobiotics and lower their ability to cross biological membranes. Medicinal chemists can, similarly, enhance the solubility of phenols and alcohols by O-sulfation. However, the oral bioavailability will usually be lowered by O-sulfation. This strategy has only rarely been used in drug design. Monoaryl- and monoalkylsulfates (ArOSO3H, ROSO3H) are chemically quite stable and usually less toxic than the corresponding phenols and alcohols. A number of drugs are metabolized to biologically active O-sulfates (e.g., triamterene, minoxidil), and in the future, an increasing number of such sulfated metabolites will probably be developed as liquid formulations for parenteral administration. Picosulfate and bisacodyl are laxatives for oral administration (Scheme 42.1). Bisacodyl is deacetylated by intestinal bacteria. These compounds are poorly absorbed from the gastrointestinal tract and act by stimulating peristaltic mobility and by increasing the excretion of water into the intestine. Both compounds show similar biological properties, a further indication that phenols and their sulfates can be bioisosteres. Sulfates will, however, be less orally bioavailable and less membrane penetrating because of their complete ionization at physiological pH.

O NH O 2 NH2 O O S N H2N O F O N O O O O O N O SO H 3 O O SO3H Safinamide NXL-104 Topiramate t 1/2 22 h, F 80–92% t 1/2 2–3 h (iv) t 1/2 20–24 h, F 80–95%

N N

O O NaO S SO Na 3 O O 3 O O Picosulfate Bisacodyl F 10% F < 5% Scheme 42.1 Therapeutic sulfates and sulfamic esters.

Closely related to sulfates are sulfamic acids (R2NSO3H) and their esters (Scheme 42.2). These compounds can be metabolically rather stable, such as the artiﬁcial sweeteners acesulfame and cyclamate. The latter is, though, partially metabolized to cyclohexylamine.

O O S CO2H ONH

O O H N N H Acesulfame O O N N t 2.5 h, F 100% 1/2 S H2N N N S O N H H O SO H H OH 3 N Aztreonam SO3H Quinagolide t 1/2 1.7 h, F < 1% t 1/2 12–17 h, F 100% Cyclamate t 1/2 8 h (rat, dog), F < 37%

Scheme 42.2 Sulfamic acids and sulfamic esters. 209

43 Phosphonic Acids

Phosphonic acids (pKa 2–3 and 8–9) are strong acids and will be completely ionized under physiological conditions. Their oral bioavailability is low because of high fraction of anionic phosphonate. Most of these strong acids can cause esophagitis, gastritis, or peptic ulcers. The phosphonic acid group can be used as mimetic of phosphate monoesters (such as nucleotides or pyrophosphates) in antiviral drugs or as carboxylate analog (Scheme 43.1). Phosphonate monoesters, such as ceronapril, are stable if phosphate-hydrolyzing enzymes (e.g., DNAses or RNAses) do not accept them as substrates.

O H N OH OH 2 O N P H N OH 2 N P N N OH OH O OH O P H O OH O O OH Fosmidomycin Alafosfalin Cidofovir − t1/2 2 h, F 20 30% − t1/2 1 h, F 50% t1/2 2 3 h, F < 5%

NH2 O O O OH OH OH P HO P P N O O OH O OH O CO2H Fosfomycin Foscarnet Ceronapril − − t1/2 2 4 h, F 30 44% t1/2 3.3 h, F 17% t1/2 15 h, F 67%

Scheme 43.1 Therapeutic phosphonic acids.

To improve oral bioavailability, prodrugs of phosphonic acids have been developed. Two examples of such prodrugs (antivirals) are shown in Scheme 43.2.

O O O O OH N HO N NH O N in vivo P O 2 O N NH P O 2 O NN O NN Adefovir t 5−11 h, F 60% Adefovir dipivoxyl 1/2 (drug on oral dose of prodrug)

O O O O O O OH N HO N O N in vivo P O NH2 O N NH P O 2 O NN O NN Tenofovir t 12−26 h, F 25% Tenofovir disoproxil 1/2 (drug on oral dose of prodrug)

Scheme 43.2 Prodrugs of antiviral phosphonic acids.

A special group of phosphonic acids are the bisphosphonates, for instance, alendronic acid (Table 43.1). These compounds inhibit bone resorption and are used to treat Paget’s disease (abnormal bone formation) and osteoporosis. Because of their strong acidity and low lipophilicity, most bisphosphonates are poorly absorbed from the intestine and are usually dosed parenterally. Despite their variable plasma half-lives, once incorporated into bones, bisphosphonates remain there for a long time.

− Table 43.1 Phosphonic acids. V inlkg−1;CLinmlmin−1 kg 1; Mwt in g mol−1.

1/ . ± . . ± . t 2 3 3 1 5h V 0 43 0 13 FOSCARNET F 17±4% CL 2.0±0.6 Antiviral HO CO2H P ± HO pb 15 2% Mwt 126.0 2 O ur 82±13% PSA 105 A˚ log P −1.90

t1/ 12 h (iv) V 0.32 FOSFOMYCIN O 2 OH F – CL 2 Antibacterial P OH pb 0% Mwt 138.1 2 O ur – PSA 79.9 A˚ log P −1.23 43 Phosphonic Acids 211

t1/ 1h V – ALAFOSFALIN O 2 F 50% CL – Antibacterial H N OH 2 N P pb <10% Mwt 196.1 Metabolism: amide hydrolysis H OH 2 O ur 6–17% PSA 122 A˚ log P −2.89

1/ t 2 1.5–2.0 h V – FOSMIDOMYCIN OH O F 20–30% CL – Antimalarial OH < O pb 3% Mwt 183.1 N P 2 OH ur 26% PSA 98.1 A˚ log P −1.58

1/ O O t 2 5.7 h V 0.43 PERZINFOTEL, EAA 090 O F 3–5% CL 2.5 NMDA antagonist, OH P pb – Mwt 260.2 neuroprotectant, analgesic HN N OH 2 ur – PSA 117 A˚ log P −1.84

1/ ∗ O t 2 10.5 years V 0.4 ALENDRONIC ACID HO OH F 0.8–1.8% CL 2.8 ∗in bone P OH pb 78% Mwt 249.1 Bone resorption inhibitor H2N OH P ˚ 2 OH ur 40–60% PSA 161 A O log P −3.46

O t1/ 28±7h V – PAMIDRONIC ACID HO OH 2 F 0.2% CL 6.7 Bone resorption inhibitor P OH OH pb 54% Mwt 235.1 H N P 2 2 OH ur 100% PSA 181 A˚ O log P −0.89

1/ O t 2 – V – OLPADRONIC ACID HO OH F 2–4% CL – Bone resorption inhibitor P OH OH pb – Mwt 263.1 N P ˚ 2 OH ur – PSA 158 A O log P −2.77

O t1/ 10–60 h V 1.3–2.0 IBANDRONIC ACID HO OH 2 F 0.6% CL 0.17–0.18 Bone resorption inhibitor P OH OH pb 90–99% Mwt 319.2 N P 2 OH ur 60% PSA 158 A˚ O log P 2.33

1/ ∗ O t 2 1.6–2.0 h V – INCADRONIC ACID HO OH ∗ P F Low CL – iv OH pb – Mwt 287.2 Bone resorption inhibitor N P ˚ 2 H OH ur 55–70% PSA 147 A O log P −0.97

(continued overleaf ) 212 43 Phosphonic Acids

O t1/ 146–167 h V 0.09–0.15 ZOLEDRONIC ACID HO OH 2 P F <1% CL 1.0–1.3 Bone resorption inhibitor N OH N OH pb 43–56% Mwt 272.1 P 2 OH ur 39% PSA 168 A˚ O log P −2.28

O t1/ 66–480 h V 6.3 RISEDRONIC ACID N HO OH 2 F <1% CL 3.8 Bone resorption inhibitor P OH OH pb 24% Mwt 283.1 P 2 OH ur 87% PSA 168 A˚ O log P 0.55

O t1/ 13–15 h V 0.3–0.8 CLODRONIC ACID HO OH 2 P F 1–2% CL 1.4–1.7 Bone resorption inhibitor, Cl OH pb 2–36% Mwt 244.9 calcium regulator P 2 Cl OH ur 70–90% PSA 135 A˚ O log P 1.11

O t1/ 1–6 h V 0.3–1.3 ETIDRONIC ACID HO OH 2 P F 1.5–3.5% CL 1.5 Calcium regulator for HO OH pb – Mwt 206.0 treatment of hypercalcemia P 2 OH ur 100% PSA 155 A˚ O log P −0.75

O t1/ 50±10 h V – TILUDRONIC ACID Cl HO OH 2 P F 6% CL – Bone resorption inhibitor OH pb 90% Mwt 318.6 S P 2 OH ur 60% (iv) PSA 160 A˚ O log P 2.00

44 Phosphoric Acid Derivatives

Phosphoric acid monoesters or -amides (XPO(OH)2;X= RO, RS, R2N) usually have short half-lives in plasma because of rapid hydrolysis by ubiquitous phosphatases. Phosphates may, therefore, be used as prodrugs of alcohols, thiols, or NH groups (Scheme 44.1). Phosphates can enhance the solubility of drugs in water (to improve absorption or enable liquid formulations for parenteral administration), and, by conversion into salts, raise their melting points. The latter aspect is particularly useful for drugs that are liquid or low-melting alcohols or phenols.

H N H O in vivo N N O O O N O HO P H OH O Fosphenytoin Phenytoin t1/2 8–15 min , F low t1/2 15 h, F 90%

F F N F F N N in vivo N N N HO O N N N P OH N HO O N N Fosfluconazole Fluconazole t1/2 2.1 h (iv) t1/2 32 h parenteral prodrug F > 90%

Scheme 44.1 Phosphate-based prodrugs and their metabolism.

OH O P OH H N H N 2 O in vivo 2 OH H H N N O N N O S S O O O O O O O O

Fosamprenavir Amprenavir oral prodrug t1/2 7–11 h, F 35–90% (dog)

O O OH P O HO O OH Fostriecin OH t1/2 1.5 h (iv) HO

H O OH in vivo H in vivo H N N P H N N Disulfide 2 S OH 2 SH Amifostine t1/2 < 10 min OH O P OH H N O N N O N O O F C N in vivo F C N 3 O N 3 O N H H

CF3 CF3 F F Fosaprepitant Aprepitant parenteral prodrug t1/2 9–13 h, F 60–65%

Scheme 44.1 (Continued). 215

45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

It was known for long that oral cocaine numbs the mouth. In 1883, Carl Koller, a student of ophthalmology at the University of Vienna, discovered that cocaine was well suited as a topical anesthetic for the eye. If a solution of cocaine is trickled into the eye of a frog or human, the cornea can be touched without causing the normal eye-closing reflex [1]. This finding led to intensive search for more readily accessible, less toxic, and less addicting alternatives to cocaine. Some of the earliest analogs used as local anesthetics are shown in Scheme 45.1. The main initial problems of these drugs were low potency, skin irritation, and low solubility in water. Most of these issues were finally solved with procaine, which became one of the most widely used local anesthetics, until the discovery of lidocaine in 1948 (Chapter 54).

O N O NH O H2N H O O MeO C 2 HO H Cocaine β-Eucaine Orthocaine new t 1/2 0.8 h, F 57% (1896, Schering) (1896, Hoechst) structure elucidated 1895 by Willstätter

O O O N O O N O

H2N H2N Benzocaine Amylocaine Procaine (1902, Bayer) (1902, Poulenc Frères) (1904, Hoechst)

Scheme 45.1 Local anesthetics.

The metabolically more stable amide analog of procaine, procainamide, is not only a local anesthetic but also an antiarrhythmic, by virtue of its Na+-channel

blocking properties. Interestingly, additional small structural variations can lead to a loss of anesthetic and antiarrhythmic activity and give rise to dopamine antagonism, as in metoclopramide, and to serotonin agonism. A large number of drugs for a variety of indications contain the N-(aminoalkyl)benzamide substructure (Table 45.1). These compounds are mainly monoamine oxidase (MAO) inhibitors (antidepressants), 5-hydroxytryptamine (5-HT) agonists (antiemetics and gastroprokinetics), and dopamine antagonists (antipsychotics and gastroprokinetics). Aminoalkylbenzoates such as procaine have short plasma half-lives (<5min) owing to rapid ester hydrolysis. N-(Aminoalkyl)benzamides are more stable and are mainly metabolized by N-dealkylation, N-oxidation, and aromatic hydroxylation. Aminobenzoic acid derivatives are N-acetylated reversibly.

Reference

1. Sneader, W. (1994) Local anesthetics. Drug News Perspect., 7, 60–64.

Table 45.1 Aminoalkylbenzamides, aminoalkylbenzoates, and related compounds. V in l kg−1; − CL in ml min−1 kg 1; Mwt in g mol−1.

1/ ± t 2 3 1h V 1–2 MOCLOBEMIDE O O F 60±20% CL 5–13 MAO inhibitor, antidepressant N pb 50% Mwt 268.7 Metabolism: morpholine N 2 H ur <1% PSA 41.6 A˚ N-oxidation, aromatic Cl log P 1.34 hydroxylation, and morpholine N-dealkylation

1/ . ± . . ± . t 2 3 0 0 6h V 1 9 0 3 PROCAINAMIDE O F 83±16% CL 2.7 Na channel blocker, antiarrhythmic N pb 16±5% Mwt 235.3 Metabolism: N-acetylation (to N 2 H ur 67±8% PSA 58.4 A˚ acecainide), N-deethylation, and H N 2 log P 1.32 N-oxidation, only 1% amide hydrolysis

t1/ 20–25 s V – CHLOROPROCAINE O 2 F – CL – Local anesthetic N O pb – Mwt 270.8 Metabolism: ester hydrolysis . ˚ 2 H2N Cl ur – PSA 55 6 A log P 2.83

1/ . ± . . ± . t 2 6 0 0 2h V 1 4 0 2 ACECAINIDE, O ± . ± . N F 83 12% CL 3 1 0 4 N-ACETYLPROCAINAMIDE O N ± H pb 10 9% Mwt 277.4 Antiarrhythmic 2 N ur 81±1% PSA 61.4 A˚ Metabolism: N-deethylation H log P 1.51 and N-deacetylation 217

1/ O t 2 40 h V – CPI-1189 F 55% (rat) CL – Treatment of dementia and irritable O N H pb – Mwt 234.3 bowel disease, crosses bbb 2 N ur – PSA 58.2 A˚ H log P 1.54

1/ . ± . . ± . t 2 5 0 1 4h V 3 4 1 3 METOCLOPRAMIDE ± . ± . O F 76 38% CL 6 2 1 3 Dopamine antagonist, antiemetic, Cl N pb 40±4% Mwt 299.8 gastroprokinetic; Metabolism: N 2 H ur 20±9% PSA 67.6 A˚ aniline sulfation and H2N OMe log P 2.16 glucuronidation, oxidation of CH2NEt2 to CO2H

1/ O t 2 3–5 h V 3.1 BROMOPRIDE Br N F 54–75% CL 13 Dopamine antagonist, antiemetic N H pb 40% Mwt 344.3 . ˚ 2 H2N OMe ur 10–14% PSA 67 6 A log P 2.54

1/ . ± . t 2 3 6 0 8h V 0.8 SEMATILIDE O F 47±15% CL 3.7 Antiarrhythmic N O O N pb 4% Mwt 313.4 H S ± . ˚ 2 N ur 36 12% PSA 86 9 A H log P 1.15

1/ t 2 2–5 h V 1.4 TIAPRIDE O O O F 75% CL 4.3 Antidyskinetic S N N pb Negligible Mwt 328.4 Metabolism: N-deethylation H 2 ur 54–76% PSA 84.1 A˚ OMe log P 1.22

1/ F t 2 40–60 h V 34 SUNITINIB O F 70% CL 9–16 Kinase inhibitor, antineoplastic; 1/ N pb 95% Mwt 398.5 active metabolite: N-desethyl (t 2 N 2 H ur <16% PSA 77.2 A˚ 80–110 h, pb 90%) HN HN O log P 3.16

1/ t 2 6–8 h V 0.94 SULPIRIDE O O O F 25–36% CL 1.9 Dopamine D2 antagonist, S N pb 11–18% Mwt 341.4 antipsychotic, antidepressant, H N N 2 2 H ur 15% PSA 110 A˚ antiemetic; Metabolism: oxidation OMe log P 0.78 of pyrrolidine to 2-pyrrolidone, no amide hydrolysis

(continued overleaf ) 218 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

1/ O O O t 2 4h V – VERALIPRIDE S F – CL – Suppression of menopausal hot H N N N 2 H pb – Mwt 383.5 ﬂushes; withdrawn 2 OMe ur – PSA 119 A˚ OMe log P 0.73

1/ t 2 4–11 h V – SULTOPRIDE O O O F – CL – Dopamine D2 antagonist, < S N pb 25% Mwt 354.5 antipsychotic; Metabolism (rat): N 2 H ur 90% PSA 84.1 A˚ O-demethylation, S-deethylation, OMe log P 1.39 oxidation of pyrrolidine, amide hydrolysis

1/ O t 2 12 h V 5.8 AMISULPRIDE O O ± S F 50 2% CL 20 Dopamine D2/D3 antagonist, N N H pb 16% Mwt 369.5 antipsychotic; Metabolism: ˚ 2 H2N OMe ur 26–50% PSA 110 A oxidation of pyrrolidine to log P 1.50 2-pyrrolidone, N-deethylation

1/ MeO O t 2 4–7 h V 0.7 REMOXIPRIDE > Br F 90% CL 1.5–1.7 Dopamine D2 antagonist, N N H pb 84% Mwt 371.3 antipsychotic; Metabolism: 2 OMe ur 10–40% PSA 50.8 A˚ oxidation to lactam, N-deethylation, log P 2.19 hydroxylation of pyrrolidone

1/ MeO O t 2 6–13 h V 1.5 RACLOPRIDE Cl F 65–67% CL/F 2.2±0.5 Dopamine D2 antagonist, N N H pb – Mwt 347.2 neuroleptic 2 OH ur <1% PSA 61.8 A˚ Cl log P 3.58

1/ O t 2 2–3 h V 1.6 ALIZAPRIDE F 75–100% CL 6.6 Antipsychotic, antiemetic N N N N H pb 75% Mwt 315.4 2 N OMe . ˚ H ur High PSA 83 1 A log P 0.84

1/ F t 2 1.4–2.0 h V 1.7–3.5 MOSAPRIDE F 14%∗ CL 14–21 ∗monkey pb 99% Mwt 421.9 5-HT4 agonist, gastroprokinetic 2 O ur <1% PSA 76.8 A˚ Metabolite: des-4-ﬂuorobenzyl Cl N N log P 2.82 H O H2N OEt 219

t1/ 5–8 h V – CINITAPRIDE O N 2 F –CL–5-HT1 and 5-HT4 agonist, O2N N pb – Mwt 402.5 gastroprokinetic H 2 ur – PSA 113 A˚ Metabolism: N-dealkylation H2N OEt log P 3.76

1/ . ∗ t 2 24 h V 1.6–3 2 CLEBOPRIDE O N ∗ Cl F –CL– rat, dog N pb – Mwt 373.9 Antiemetic, antispasmodic H 2 ur – PSA 67.6 A˚ Metabolites: glucuronide, H2N OMe log P 2.70 desbenzyl; no amide hydrolysis

1/ O t 2 6–9 h V – NEMONAPRIDE N Cl F –CL–D2 antagonist, 5-HT1A agonist N H pb – Mwt 387.9 Metabolism: N-demethylation 2 N OMe ur – PSA 53.6 A˚ H log P 3.78

1/ ± O t 2 16 3h V – PANCOPRIDE Cl N F 82–92% CL – 5-HT3 antagonist, antiemetic N H pb – Mwt 349.9 . ˚ 2 H2N O ur 10–17% PSA 67 6 A log P 2.85

1/ ± O t 2 37 12 h V 6.9–7.9 PALONOSETRON Cl N F 97% CL 2.7 5-HT antagonist, antiemetic N 3 pb 62% Mwt 296.4 Metabolism: N-oxidation (tertiary 2 H ur 40% PSA 23.6 A˚ amine), benzylic log P 2.61 (6) hydroxylation

1/ O t 2 6–8 h V –AZASETRON Cl N F 90% CL – 5-HT3 antagonist, antiemetic N H pb – Mwt 349.8 2 O ur 60–70% PSA 61.9 A˚ N log P 1.83

t1/ 10 h V – RENZAPRIDE O N 2 Cl F –CL–5-HT4 agonist, 5-HT3 antagonist, N pb – Mwt 323.8 gastroprokinetic H 2 ur – PSA 67.6 A˚ H2N OMe log P 1.83

(continued overleaf ) 220 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

1/ ± . ± . O t 2 11 3h V 4 9 0 4 FLECAINIDE H ± . ± . F C O N F 70 11% CL 5 6 1 3 Antiarrhythmic 3 N ± H pb 61 10% Mwt 414.3 Metabolism: m-O-dealkylation, ± . ˚ 2 O CF3 ur 43 3% PSA 59 6 A oxidation to lactam log P 3.19

1/ O t 2 2–12 h V 2–4 ENCAINIDE F 30–55% CL 11–13 Antiarrhythmic N H pb 70–80% Mwt 352.5 Metabolism: O-demethylation; 2 MeO N ur <10% PSA 41.6 A˚ withdrawn in 1991 because of log P 3.75 excessive patient mortality

1/ t 2 7–10 h V 2.4 CISAPRIDE F F 40–50% CL – Peristaltic stimulant; Metabolism: O N pb 98% Mwt 466.0 N-dealkylation of piperidine, Cl N O . ˚ 2 H ur 1–3% PSA 86 1 A hydroxylation of phenoxy, cleavage OMe H2N OMe log P 2.83 of ﬂuorophenyl ether, no amide hydrolysis; withdrawn in 2000 for causing cardiac arrhythmias

t1/ 5.4 h V – NARONAPRIDE O N 2 Cl F – CL – 5-HT4 agonist, gastroprokinetic N H pb 30–40% Mwt 537.1 Metabolism: ester hydrolysis, OMe O ˚ 2 H2N OMe ur – PSA 106 A aniline glucuronidation, and O log P 2.02 oxidative degradation of alkanoic N acid side chain

1/ O N t 2 22–34 h V 8.7 PRUCALOPRIDE > Cl F 90% CL 4.9 5-HT4 agonist, gastroprokinetic N OMe H pb 30% Mwt 367.9 Metabolism: O-demethylation, then . ˚ 2 H2N O ur 60% PSA 76 8 A oxidation of alcohol to carboxylic log P 1.44 acid

1/ ± O t 2 9 3h V 1.4 TRIMEBUTINE MeO N F 4–6% CL – Antispasmodic O pb <5% Mwt 387.5 Metabolism: N-demethylation, 2 MeO ur <2.4% PSA 57.2 A˚ ester hydrolysis OMe log P 4.84

1/ t 2 20 h V – PROPIVERINE O N O F 36–42% CL – Anticholinergic, treatment of O pb 90% Mwt 367.5 urinary incontinence 2 ur 6–8% PSA 38.8 A˚ Metabolites: N-oxide, 1/ log P 4.37 N-desmethyl (t 2 20 h), O-despropyl 221

1/ t 2 34 h (iv) V 7.1 DENAVERINE F 37% CL 5.7 Antispasmodic O O pb – Mwt 383.5 Metabolism: N-demethylation N 2 O ur 33% (rat) PSA 38.8 A˚ (ﬁrst-pass), ester hydrolysis, log P 4.88 and O-dealkylation

t1/ 2.3 h V – CARBETAPENTANE, O 2 F <50% CL – PENTOXYVERINE O O N pb – Mwt 333.5 Antitussive 2 ur <0.5% PSA 38.8 A˚ Metabolism: ester hydrolysis log P 4.11

t1/ 5–10 h V 3.7 DICYCLOMINE, DICYCLOVERINE O 2 N F 67% CL – Anticholinergic O pb >99% Mwt 309.5 2 ur – PSA 29.5 A˚ log P 4.64

t1/ 2h V 1–3 OXYBUTYNIN O 2 F 6% CL 5–6 Anticholinergic O > HO N pb 99% Mwt 357.5 Metabolism: N-deethylation, 2 ur <0.1% PSA 49.8 A˚ hydrolysis of ester, and log P 5.05 hydroxylation of cyclohexane

t1/ 2–5 h V 0.9 NAFRONYL, NAFTIDROFURYL O 2 N F – CL – Vasodilator, crosses bbb O pb 60–80% Mwt 383.5 Metabolism: ester hydrolysis, 2 ur <1% PSA 38.8 A˚ oxidation to 2-furanone O log P 3.91

1/ O t 2 1.6 h V – PROPANTHELINE N F 5–15% CL – Anticholinergic O pb – Mwt 368.5 Metabolism: ester hydrolysis, O 2 ur 3–5% PSA 35.5 A˚ aromatic hydroxylation log P 0.79

1/ O t 2 0.6–1.2 h V 0.4–1.8 GLYCOPYRROLATE N F 1–13% CL 9 Anticholinergic O HO pb – Mwt 318.4 ur 65–80% PSA 46.5 log P −0.85

(continued overleaf ) 222 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

1/ t 2 5d V 32 TIOTROPIUM ∗ ∗ H N F 2–3% CL 10.9 20% on inhalation S O ∗∗ O pb 71–79% Mwt 392.5 14% on inhalation O ∗∗ 2 HO ur 74% (iv) PSA 59.1 A˚ Muscarinic antagonist, S log P −1.94 bronchodilator Metabolism: ester hydrolysis

1/ t 2 2.5 h V 3.6 OXITROPIUM O H N F 0.5%∗ CL 31 ∗12% on inhalation O O pb 7% Mwt 332.4 Bronchodilator 2 ur 0.3% PSA 59.1 A˚ Metabolism: ester hydrolysis HO log P −2.56

1/ t 2 2h(iv) V – CIMETROPIUM O H N F 1–4% CL – Antispasmodic O O pb – Mwt 358.5 Metabolism: aromatic 2 ur 50% (iv) PSA 59.1 A˚ hydroxylation, ester HO log P −2.06 hydrolysis

1/ ∗ t 2 1.5–4.0 h V 4.6 IPRATROPIUM F 1–6% CL 31 ∗iv; ∗∗50% (iv) pb <20% Mwt 332.5 Muscarinic antagonist, 2 ur 24%∗∗ PSA 46.5 A˚ bronchodilator, antiarrhythmic O H N log P −1.47 Metabolism: ester hydrolysis, O elimination of water to α HO -phenylacrylic acid, dehydroxymethylation to phenylacetic ester

1/ ± . ± . t 2 3 1h V 1 4 0 7 SCOPOLAMINE F 27±12% CL 16±13 Anticholinergic, treatment of O H N pb – Mwt 303.4 motion sickness; Metabolism: O 2 O ur 6±4% PSA 62.3 A˚ aromatic 3- and 4-hydroxylation, HO log P 1.05 then phenolic O-methylation, ester hydrolysis, N-demethylation, and dehydration

1/ t 2 5h V 2 BUTYLSCOPOLAMMONIUM, O H N F <1% CL 19 BUTYLSCOPOLAMINE O O pb Low Mwt 360.5 Antispasmodic 2 ur 50% PSA 59.1 A˚ Metabolism: ester hydrolysis HO log P −1.49 223

1/ t 2 2–5 h V 2–4 ATROPINE (racemate) O H N F 50% CL 7.6 Anticholinergic; Metabolism: pb 14–40% Mwt 289.4 N-demethylation, N-oxidation, O 2 ur 50% PSA 49.8 A˚ and ester hydrolysis; the HO log P 1.38 shown enantiomer (hyoscyamine) has similar PK as atropine

t1/ 6–8 h V 6.6–9.7 TROPISETRON O H N 2 F 27–99% CL 3–26 5-HT3 antagonist, antiemetic, O pb 59–71% Mwt 284.4 CYP2D6 substrate; Metabolism: 2 N ur 8–10% PSA 45.3 A˚ aromatic 5-, 6-, and 7-hydroxylation, H log P 3.03 N-demethylation

1/ ∗ t 2 4–9 h V 1.6–7.3 DOLASETRON F 70–89% CL 6–14 5-HT antagonist, antiemetic; O 3 H N ∗ 1/ < O pb 69–77% Mwt 324.4 prodrug (t 2 10 min): fast in vivo . ˚ 2 O ur 19–38% PSA 62 4 A reduction of ketone to alcohol; all log P 2.82 values for alcohol on oral dosing of N H ketone; further metabolism: aromatic hydroxylation, N-oxidation of tertiary amine

1/ . ± . . ± . t 2 5 3 3 5h V 3 0 1 5 GRANISETRON ± O H N F 60% CL 11 95-HT3 antagonist, antiemetic pb 65±9% Mwt 312.4 Metabolism: N-demethylation of N 2 H ur 16±14% PSA 45.2 A˚ indazole, aromatic 6- and N N log P 1.47 7-hydroxylation, then glucuronidation

1/ t 2 11–14 h V – ITASETRON O H N F 64–72% CL – 5-HT3 antagonist, antiemetic N N pb – Mwt 300.4 H . ˚ 2 N O ur 59–73% PSA 64 7 A H log P 1.31

1/ t 2 25–37 h V – ZATOSETRON O H N F –CL–5-HT3 antagonist, antiemetic Cl N pb 75% Mwt 348.9 Metabolism: N-oxidation, 2 H ur 36% PSA 41.6 A˚ N-demethylation, benzylic O log P 3.19 hydroxylation, then oxidation of alcohol to ketone

(continued overleaf ) 224 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

t1/ 1.3 h V – TIARAMIDE O 2 S O F – CL – Antiasthmatic, antiinﬂammatory N pb 24–34% Mwt 355.8 Metabolism: O-glucuronidation, N < . 2 N ur 1% PSA 89 4 A˚ N-de(hydroxyethylation), oxidation Cl OH log P 1.18 to N-oxide, and N-acetic acid

t1/ 9±4h V 9 BISARAMIL H 2 O F 56±20% CL 17 Antiarrhythmic O pb – Mwt 322.8 Metabolism: ester hydrolysis N 2 ur – PSA 32.8 A˚ Cl N log P 2.05

t1/ 1.5 h (iv) V 1.6 COCAETHYLENE O 2 F – CL 13 Recreational drug (highly addictive) O N pb 36% Mwt 317.4 2 H ur – PSA 55.8 A˚

EtO2C log P 2.79 H

t1/ 0.8±0.2h V 2.0±0.2 COCAINE O 2 F 57±19% CL 32±6 Local anesthetic, recreational drug O N pb 91% Mwt 303.4 (highly addictive) 2 H ur <2% PSA 55.8 A˚

MeO2C log P 2.28 H

46 Arylalkylamines

For each amine-containing natural neurotransmitter, several different receptors are known: four histamine receptors, five dopamine receptors, seven serotonin receptors, and five adrenaline receptors (two α and three β receptors). Each receptor is expressed to a different extent in different tissues and elicits a different biological response. Because of the close structural relationship between the hormones, many amine-based unnatural ligands at these receptors have similar structures, and many are nonselective. For most of these receptors, both agonists and antagonists have been developed. In the following section, most known arylalkylamines are listed, to illustrate pharmacokinetics (PK) changes on minimal and continuous structural modification. Therefore, no arrangement according to the target protein or indication was attempted. Amines with one, two, or more aryl/heteroaryl groups are useful drugs for a wide variety of indications. The most important drugs of this type include antiallergics, antipruritics, nootropics, antipsychotics, antidepressants, anxiolytics, sedatives, hypnotics, antiepileptics, antiemetics, analgesics, vasodilators, and antiarrhythmics.

46.1 Antihistaminics: History

In the 1930s, several academic laboratories and pharmaceutical companies began seeking compounds that could antagonize the most obvious biological effects of histamine, namely, bronchoconstriction and vasodilation, to gain a better understanding of the physiological role of histamine. Among the ﬁrst compounds to be marketed as ‘‘antihistaminics’’ (histamine H1 antagonists) were pyrilamine (1944), tripelenamine (1946), diphenhydramine (1946), and metapyrilene (1947). These drugs, followed by many analogs, became hugely popular for the suppression of the symptoms of common cold and hay fever and are still used for this purpose today. Because of the sedating effect of these ‘‘ﬁrst generation’’ antihistaminics, caused by their ability to cross the blood–brain barrier (bbb) and block the H1 receptors in the central nervous system (CNS), these drugs were also used as

hypnotics. One patient treated with diphenhydramine reported that she did no longer get motion sick on the streetcar, and this effect could be conﬁrmed in a group of sailors in 1947. Since then, antihistaminics were also used as remedy for motion sickness and as antiemetics (e.g., cyclizine, 1949) [1]. To overcome the sedating effect of these bbb-crossing H1 antagonists, more hydrophilic drugs were developed, the ﬁrst ones being terfenadine (1982), 2 astemizole (1983), and loratadine (1986). Their large polar surface areas (>40 A˚ ) keep them from entering the CNS. The most common metabolic transformations of arylalkylamines include N-dealkylation, N-oxidation, and aromatic hydroxylation. Despite the large number of drugs containing an arylalkylamine substructure, most of them can be assigned to one of the generic structures given in Scheme 46.1. In these, Ar represents optionally substituted aryl or heteroaryl groups, R is alkyl, and X and Y are C, N, O, or CO. The compounds listed in Tables 46.1–46.4 appear in the same order as the generic structures in the sketch.

Ar X NR Ar NR Ar X O Ar Y 2 Y 2 Y NR 2 N Ar Ar Ar Ar “Peridols” Histamine H1 antagonists Histamine H1 antagonists Histamine H1 antagonists 5-HT reuptake inhibitors Calcium channel blockers 5-HT reuptake inhibitors Antipsychotics Calcium channel blockers Opioid analgesics Calcium channel blockers Opioid analgesics Noradrenaline and Opioid analgesics Dopamine reuptake inhibitors Respiratory stimulants Muscarinic antagonists Antiarrhythmics Anticholinergics Dopamine antagonists Antipsychotics

R X Ar N Y Ar X Ar X N N Ar NR2 Ar ()n R O Ar

Opioid analgesics “fentanils” Opioid analgesics Histamine H1 antagonists Antiestrogens 5-HT antagonists 5-HT antagonists 5-HT antagonists Antiarrhythmics Dopamine antagonists 5-HT reuptake inhibitors Calcium channel blockers Dopamine antagonists Respiratory stimulants

Scheme 46.1 Typical generic structures of arylalkylamine drugs.

Reference

1. Sneader, W. (2001) Histamine and the classic antihistamines. Drug News Perspect., 14, 618–624. 227

Table 46.1 (Arylalkyl)amines. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 3.0–4.5 h V 10 TRIPELENNAMINE N F –CL32Histamine H1 antagonist N pb – Mwt 255.4 Metabolism: aromatic 2 N ur – PSA 19.4 A˚ p-hydroxylation, benzylic log P 2.78 C-hydroxylation, N-depyridylation, N-debenzylation

1/ t 2 1.6 h (iv) V 3.3 METAPYRILENE, THIONYLAN F 4–46% CL 28 Histamine H1 antagonist S N pb – Mwt 261.4 Metabolites: N 2 ur – PSA 47.6 A˚ hydroxymethylthiophene, N log P 2.78 thiophene-2-carboxylic acid, 2-(2-thienylmethyl)aminopyridine), N-desmethyl; withdrawn in 1979 for being hepatocarcinogenic

1/ t 2 14–25 h V – PYRILAMINE, MEPYRAMINE N F –CL–Histamine H1 antagonist N pb – Mwt 285.4 Duration of action: 4–6 h 2 MeO N ur – PSA 28.6 A˚ Metabolism: O-demethylation log P 2.67

1/ ± t 2 12 h V 8 5BEPRIDIL F 60% CL 5.3±2.5 Calcium channel blocker, pb >99% Mwt 366.5 antianginal N 2 N ur <1% PSA 15.7 A˚ Metabolism: aromatic log P 5.80 hydroxylation to 4-aminophenols, O N-debenzylation, then N-acetylation, isobutyl hydroxylation, pyrrolidine hydroxylation

1/ t 2 5–7 h V 2.3 PROPIRAM O F >97% CL 6.3 Analgesic, narcotic N N pb – Mwt 275.4 Metabolism: piperidine 2 ur 24% PSA 36.4 A˚ hydroxylation, then oxidation to N log P 3.01 lactam, then hydrolysis of lactam

t1/ 25 min V – CAROVERINE O 2 F Low CL – Calcium channel blocker, N N pb – Mwt 365.5 antispasmodic N 2 MeO ur – PSA 45.1 A˚ log P 3.61

(continued overleaf ) 228 46 Arylalkylamines

1/ ± / ± t 2 53 41 h V F 35 21 FLUOXETINE H F 70% CL/F 9.6±6.9 5-HT reuptake inhibitor, O N pb 94% Mwt 309.3 antidepressant 2 ur 2–5% PSA 21.3 A˚ Substrate and inhibitor of CYP2D6 F C 3 log P 3.93 Active metabolite: N-desmethyl 1/ . ± . (t 2 6 5 2 5d,CL2ml min−1 kg−1)

t1/ 5.2 h V 0.85 ATOMOXETINE H 2 O N F 63–94% CL 6–9 Noradrenaline reuptake inhibitor pb 98% Mwt 255.4 for treatment of attention deﬁcite 2 ur <3% PSA 21.3 A˚ hyperactivity disorder log P 3.28 Metabolism: 4-hydroxylation of aryloxy, N-demethylation

1/ t 2 8–17 h V – DULOXETINE Serotonin/noradrenaline reuptake H F 32–80% CL 16 O N pb >90% Mwt 297.4 inhibitor, antidepressant, analgesic 2 ur – PSA 49.5 A˚ Metabolism (CYP2D6, CYP1A2): S log P 4.81 4-, 5-, and 6-naphthyl hydroxylation, then glucuronidation, sulfation, methylation

1/ . ± . t 2 18 h V 2 5 0 9 DAPOXETINE F 15–76% CL – Serotonin transporter inhibitor O N pb >99% Mwt 305.4 Metabolism: N-demethylation, 2 ur Negligible PSA 12.5 A˚ N-oxidation, naphthyl log P 5.13 4-hydroxylation

t1/ 13 h V 0.7–0.9 REBOXETINE O O 2 F 95% CL 0.4–0.8 Noradrenaline reuptake inhibitor, O NH pb 97% Mwt 313.4 antidepressant 2 ur 8–9% PSA 39.7 A˚ Metabolism: O-deethylation, log P 2.45 hydroxylation of aryloxy

1/ t 2 8–24 h V 12–16 PROPOXYPHENE O F 29–70% CL 14–15 Opioid analgesic pb 76–80% Mwt 339.5 Metabolism: N-demethylation, O 2 ester hydrolysis N ur Negligible PSA 29.5 A˚ log P 4.10 Active metabolite: norpropoxyphene (see below), which is cardiotoxic; withdrawn in 2010 for inducing cardiac arrhythmias 229

t1/ 18–37 h V 10–25 NORPROPOXYPHENE O 2 F –CL0.3Metabolite of propoxyphene O H pb – Mwt 325.4 N 2 ur 20–25% PSA 38.3 A˚ log P 3.74

1/ ± t 2 60 5h V 3.7–12.6 TERODILINE H F 92±29% CL 1.1 Calcium antagonist, antianginal N pb 85% Mwt 281.4 Metabolism: aromatic 2 ur 15% PSA 12.0 A˚ 4-hydroxylation, benzylic log P 4.68 hydroxylation; withdrawn in 1991 for QT interval prolongation

1/ t 2 20–35 h V –FENDILINE H F 2–16% CL – Calcium blocker, vasodilator N pb – Mwt 315.5 Metabolism: aromatic 2 ur Traces PSA 12.0 A˚ hydroxylation, debenzylation log P 5.20

1/ t 2 30–40 h V 15.4 CINACALCET F 20–25% CL – Calcium mimetic CF3 pb 97% Mwt 357.4 Metabolism: dihydroxylation of 2 naphthalene, oxidation to H ur – PSA 12 A˚ N log P 5.74 3-(triﬂuoromethyl)cinnamide, oxidative degradation to 3-triﬂuoromethylbenzoic acid and glycine conjugate thereof

1/ ± t 2 14 7h V – PRENYLAMINE H F 15% CL – Calcium channel blocker, coronary N pb 97% Mwt 329.5 vasodilator 2 ur <0.1% PSA 12.0 A˚ Metabolism: aromatic log P 5.7 hydroxylation, N-dealkylation

1/ t 2 16–20 h V – DESOXYPIPRADROL F >90% CL – Noradrenaline/dopamine reuptake N pb – Mwt 251.4 inhibitor for treatment of attention H 2 ur – PSA 12.0 A˚ deﬁcite hyperactivity disorder log P 4.07

(continued overleaf ) 230 46 Arylalkylamines

1/ t 2 3–5 h V 6 NOMIFENSINE F <30% CL 22 Dopamine transport blocker, pb 60% Mwt 238.3 antidepressant 2 N ur <5% PSA 29.3 A˚ Metabolism: N-glucuronidation, log P 1.01 aromatic hydroxylation, aniline oxidation followed by glutathione

NH2 conjugation; withdrawn in 1986 because of kidney and liver toxicity and induction of hemolytic anemia

t1/ 45–68 h V 9.2 SOLIFENACIN O 2 F 90% CL 2.4 Anticholinergic for treatment of N N O pb 98% Mwt 362.5 overactive bladder 2 ur 11% PSA 32.8 A˚ Metabolism: benzylic hydroxylation log P 3.70 (4R-hydroxy), N-oxidation, N-glucuronidation

1/ / ± Cl t 2 23 h V F 76 26 SERTRALINE F >44% CL/F 38±14 Serotonin reuptake inhibitor, pb >99% Mwt 306.2 antidepressant Cl 2 ur <0.2% PSA 12.0 A˚ Metabolite (20–60 times less potent N log P 5.08 than parent): N-desmethyl H 1/ ± (t 2 77 2h)

1/ / t 2 2–12 d V F 4–23 PERHEXILINE F 88% CL/F 0.5–5.6 Carnitine palmitoyltransferase H N pb – Mwt 277.5 inhibitor, vasodilator, diuretic, 2 ur 0.1% PSA 12.0 A˚ antianginal log P 6.47 Metabolism (CYP2D6); 4-hydroxylation of cyclohexyl; high interpatient variability of metabolism

1/ . ± . t 2 1 9 0 4h V – EMEPRONIUM F Low CL 6.2–9.7 Anticholinergic, antispasmodic N ⊕ pb – Mwt 282.5 Metabolism: aromatic 2 ur – PSA 0.0 A˚ 4-hydroxylation log P 0.56

1/ ± t 2 17 1h V – PHENIRAMINE F –CL–Histamine H antagonist N 1 pb – Mwt 240.3 Metabolites: desmethyl, 2 ur – PSA 16.1 A˚ didesmethyl N log P 2.20 231

1/ ± . ± . Cl t 2 20 5h V 3 2 0 3 CHLORPHENIRAMINE ± . ± . F 41 16% CL 1 7 0 1 Histamine H1 antagonist N pb 70±3% Mwt 274.8 Duration of action: 5±1h 2 ur 0.3–26% PSA 16.1 A˚ Metabolism: N-demethylation N log P 2.97

1/ ± . ± . t 2 25 9h V 11 7 3 1 BROMPHENIRAMINE Br F –CL6.0±2.3 Histamine H1 antagonist pb 72% Mwt 319.2 Duration of action: 5±1h N 2 ur 3% PSA 16.1 A˚ Metabolism: N-demethylation, log P 3.24 oxidative deamination to N 3-(2-pyridyl)-3-(4-bromophenyl)- propionic acid, then conjugation with glycine

1/ ± . ± . Br t 2 5 2h V 3 2 2 0ZIMELDINE F 27±16% CL – Antidepressant N pb 90% Mwt 317.2 Metabolism: N-demethylation, 2 ur – PSA 16.1 A˚ oxidation to pyridine-N-oxide and log P 3.07 acrylic acid; withdrawn in 1983 for N causing Guillain-Barre´ syndrome

1/ ± . ± . Br t 2 16 6h V 9 6 1 8 NORZIMELDINE ± H F 64 27% CL – Metabolite of zimeldine N pb 80% Mwt 303.2 2 ur – PSA 24.9 A˚ log P 2.45 N

1/ ± t 2 5 1h V 5.8 TRIPROLIDINE F 4% CL 15.4 Histamine H antagonist N 1 pb 90% Mwt 278.4 Metabolism: CH3 hydroxylation 2 ur – PSA 16.1 A˚ and oxidation to carboxylic acid N log P 3.25

1/ . ± t 2 2 5 1h V 0.64 ACRIVASTINE F 80% CL 4.3±0.6 Histamine H1 antagonist N pb 50% Mwt 348.4 Duration of action: 7±1h 2 ur 59% PSA 53.4 A˚ Active metabolite: propionic acid N log P 2.41 formed by hydrogenation of alkene

CO2H

(continued overleaf ) 232 46 Arylalkylamines

1/ ∗ t 2 3.8 h V – TINOFEDRINE OH ∗ H F 100% CL – ∗dog S N pb – Mwt 355.5 2 ur – PSA 88.7 A˚ log P 3.42 S

1/ t 2 6.3 h (iv) V –DIMETHINDENE F –CL–∗5–10% (iv) N pb 90% Mwt 292.4 Histamine H1 antagonist 2 ur 1% (po)∗ PSA 16.1 A˚ Metabolism: N-demethylation log P 3.84 N

1/ OH t 2 2–3 h V 0.9–1.6 TOLTERODINE F 10–74% CL 8–11 Antimuscarinic for treatment of N pb 96% Mwt 325.5 urinary incontinence 2 ur 1% PSA 23.5 A˚ Metabolism: N-dealkylation by log P 5.77 CYP3A, hydroxylation by CYP2D6 (see below)

1/ t 2 7–9 h V 2.6 5-HYDROXYMETHYL OH F 52%∗ CL 2.1 TOLTERODINE N pb 64% Mwt 341.5 Active metabolite of tolterodine 2 ∗ ur 4% PSA 43.7 A˚ on oral dosing of fesoterodine OH log P 4.12 (prodrug: arylester of isobutyric acid)

1/ ∗ t 2 13 h V – FENPIPRANE F –CL–∗horse, iv N pb – Mwt 279.4 Antispasmodic 2 ur – PSA 3.24 A˚ sc administration to humans log P 4.62 (probably because of low F)

1/ t 2 14 h V – PRIDINOL, MYOSON OH F 77% CL – Anticholinergic, antiparkinsonian, N pb – Mwt 295.4 analgesic 2 ur 9% PSA 23.5 A˚ Metabolism: piperidine and log P 3.35 aromatic hydroxylation 233

1/ ± t 2 11–21 h V 24 4 BIPERIDEN OH ± ± N F 33 5% CL 12 1 Anticholinergic, antiparkinsonian pb 91% Mwt 311.5 Metabolism: hydroxylation of 2 ur 0% PSA 23.5 A˚ bicycloheptene (60%) and log P 4.27 piperidine (40%)

1/ t 2 5–10 h V – TRIHEXYPHENIDYL OH N F –CL6.3Anticholinergic, antiparkinsonian pb – Mwt 301.5 Metabolism: hydroxylation, 2 ur – PSA 23.5 A˚ N-oxidation log P 4.39

1/ t 2 12 h V 0.74 PROCYCLIDINE OH F 75% CL 0.86 N Anticholinergic, antiparkinsonian pb 100% Mwt 287.4 Metabolism (rat): cyclohexyl 3- and 2 ur – PSA 23.5 A˚ 4-hydroxylation log P 3.86

1/ O t 2 2–3 h V 2.8 OXYBUTYNIN F 2–11% CL 6 Anticholinergic O pb >99% Mwt 357.5 Metabolism: N-deethylation, ester HO N 2 ur <1% PSA 49.8 A˚ hydrolysis log P 5.05

1/ t 2 6–18 h V 1.5 PIRMENOL OH F 80–90% CL 1.8–2.9 Antiarrhythmic N pb 80–90% Mwt 338.5 Metabolism: oxidation of piperidine . ˚ 2 to iminium, then reversible N ur 20–30% PSA 36 4 A log P 3.57 tautomerization to enamine or hydrolysis to aminoketone

1/ t 2 6–10 d V 73 HALOFANTRINE F3C ∗ OH F 6±5% CL – ∗dog > N pb 99% Mwt 500.4 Antimalarial 2 1/ ur 0% PSA 23.5 A˚ Metabolite: desbutyl (t 2 3–11 d) log P 8.90 Cl Cl

1/ t 2 3–5 d V 2–4 LUMEFANTRINE HO F Variable CL – N Antimalarial Cl pb 99.7% Mwt 528.9 Metabolism: N-debutylation 2 ur – PSA 23.5 A˚ Cl log P 8.67

(continued overleaf ) 234 46 Arylalkylamines

1/ Cl t 2 6–9 d V – RIMONABANT F –CL/F 1.3–2.3 Cannabinoid CB1 antagonist, Cl pb >99.9% Mwt 463.8 appetite suppressant; withdrawn in 2 ur 3% PSA 50.2 A˚ 2008 because of depression and N N H log P 4.85 suicide risk N N Cl O

1/ NC t 2 19–45 h V 12–17 CITALOPRAM F 80–100% CL 5.7–6.3 O 5-HT reuptake inhibitor, N pb 50–80% Mwt 324.4 antidepressant 2 ur 6–31% PSA 36.3 A˚ Metabolites: desmethyl (CYP2C19), log P 3.48 didesmethyl (CYP2D6), N-oxide, deaminated propionic acid

1/ t 2 2–4 h V 1.5 DOXAPRAM F 60% CL 5.7 ∗horse N ∗ O pb 76–85% Mwt 378.5 Respiratory stimulant 2 ur <5% PSA 32.8 A˚ Metabolism: oxidative ring opening N log P 5.64 of morpholine, oxidation of O morpholine to lactam (‘‘2-ketodoxapram’’)

1/ t 2 21–31 h V 32–37 (dog) DERAMCICLANE F 23–50% CL – 5-HT2A/2C antagonist, anxiolytic pb – Mwt 301.5 Metabolite: N-desmethyl O 2 1/ ± N ur Traces (iv) PSA 12.5 A˚ (t 2 38 7h) log P 3.72

1/ ± . ± . t 2 9 3h V 4 5 2 8 DIPHENHYDRAMINE F 61±25% CL 6.2±1.7 Histamine H1 antagonist O N pb 78±3% Mwt 255.4 Duration of action: 5±1h 2 ur 2±1% PSA 12.5 A˚ Metabolism: N-demethylation, log P 3.00 oxidation of CH2NMe2 to CO2H

1/ ± . ± . t 2 16 3h V 4 5 2 8 ORPHENADRINE F 90% CL 6.2±1.7 Histamine H1 antagonist, muscle O pb 95% Mwt 269.4 relaxant, CYP2B inducer N 2 ur 8% PSA 12.5 A˚ Metabolism: N-demethylation, log P 3.33 N-oxidation to N-oxide, oxidation of CH2NMe2 to CO2H, O-dealkylation to 2-methylbenzhydrol 235

1/ t 2 3–8 h V 5.6 NEFOPAM N F 40% CL 12 Analgesic, antidepressant pb 75% Mwt 253.3 Metabolites: N-desmethyl, N-oxide 2 ur 5% PSA 12.5 A˚ O log P 1.91

1/ ± Br t 2 3 1h V 0.9 BROMODIPHENHYDRAMINE, F 65% CL – BROMAZINE O pb 96% Mwt 334.3 Histamine H1 antagonist N 2 ur – PSA 12.5 A˚ Metabolism: N-oxidation, log P 4.03 N-demethylation

1/ ± Cl t 2 15 5h V – CARBINOXAMINE F –CL–Histamine H1 antagonist; duration O pb – Mwt 290.8 of action: 3–6 h N 2 ur 5–8% PSA 25.4 A˚ Metabolism: N-demethylation N log P 2.69

1/ ± t 2 9 3h V 2.5 DOXYLAMINE F 25% CL 3.3 Histamine H1 antagonist, hypnotic O N pb – Mwt 270.4 Metabolism: N-oxidation, 2 ur 60% PSA 25.4 A˚ N-demethylation, oxidation of N log P 2.34 CCH3 to CCO2HandofCH2NMe2 to CO2H

1/ t 2 6.7–7.1 h V – CIZOLIRTINE F 60% (dog) CL – Analgesic O N pb – Mwt 259.4 Metabolism: N-oxidation, 2 ur – PSA 25.4 A˚ N-demethylation, O-dealkylation N log P 1.61 N

1/ Cl t 2 2–7 h V – CLOPERASTINE F 40% CL 14 Histamine H1 antagonist O pb >97% Mwt 329.9 N 2 ur – PSA 12.5 A˚ log P 4.58

(continued overleaf ) 236 46 Arylalkylamines

1/ ± ± Cl t 2 22 13 h V 13 5CLEMASTINE F 37±12% CL 8.3±1.6 Histamine H1 antagonist ± O N pb 95% Mwt 343.9 Duration of action: 18 6h 2 ur <2% PSA 12.5 A˚ Metabolism: O-dealkylation to log P 5.30 tertiary alcohol, aromatic hydroxylation

1/ t 2 12–66 h V 4 APRINDINE F 75% CL 1 Antiarrhythmic, local anesthetic pb 85–95% Mwt 322.5 Metabolism: N-deethylation, 2 N N ur 2% PSA 6.48 A˚ de-indanylation, hydroxylation log P 5.68

1/ t 2 53 h V – IPRINDOLE F –CL11Antidepressant pb – Mwt 284.4 Metabolism: N-demethylation, 2 N N ur – PSA 8.17 A˚ benzylic oxidation log P 5.02

1/ t 2 12–18 h V 7–9 BENCYCLANE O N F 20–80% CL 11 Vasodilator pb – Mwt 289.5 Metabolism: hydroxylation, 2 ur 3% PSA 12.5 A˚ oxidation of cycloheptane to log P 4.19 4-hydroxy and 4-oxo

1/ t 2 10–13 h V 1.7–3.3 BENZYDAMINE F 87% CL 2.5–3.0 Analgesic, antiinﬂammatory pb 10–15% Mwt 309.4 Metabolism: N-oxidation, aromatic N 2 N ur 5% PSA 30.3 A˚ hydroxylation log P 3.56 O N

1/ t 2 12–30 h V 20–25 FLUVOXAMINE MeO F 50–60% CL 15.2 5-HT reuptake inhibitor, O pb 77% Mwt 318.3 antidepressant N NH2 2 ur 3% PSA 56.8 A˚ Metabolism: oxidation of CH2OMe

F3C log P 3.71 to CO2H, N-acetylation, replacement of NH2 by OH

1/ ∗ t 2 50 h V 6 EPLIVANSERIN ∗ F >70% CL 33 ∗baboon F pb 80% Mwt 328.4 5-HT2A antagonist, hypnotic O . ˚ 2 Metabolite: N-desmethyl (t1/ 70 h) N N ur – PSA 45 1 A 2 log P 4.22 HO 237

1/ ± . ± . t 2 35 12 h V 3 8 0 6 METHADONE ± . ± . N F 92 21% CL 1 4 0 5 Analgesic, racemate pb 89±1.4% Mwt 309.5 Metabolism: N-demethylation, then 2 ur 24±10% PSA 20.3 A˚ cyclization, aromatic hydroxylation O log P 3.93

1/ t 2 8–19 h V 8.3 L-ACETYLMETHADOL F 48% CL 5.4 N Treatment of narcotic addiction pb 80% Mwt 353.5 Metabolism: N-demethylation, 2 ur 20–25% PSA 29.5 A˚ ester hydrolysis O log P 4.24

1/ t 2 3.2–3.8 h V – DIPIPANONE N F –CL–Analgesic pb – Mwt 349.5 2 ur 1% PSA 20.3 A˚ O log P 5.10

1/ ± O t 2 4 1h V – DEXTROMORAMIDE N F –CL3.8Analgesic pb – Mwt 392.5 Metabolism (horse): aromatic N 2 ur <0.1% PSA 32.8 A˚ 4-hydroxylation, N-dealkylation of O log P 2.53 amide

1/ t 2 27–36 h V – NUFENOXOLE F 100% CL 0.44 N Antidiarrheal pb 90% Mwt 387.5 Metabolism: isoquinuclidine N 2 . ˚ hydroxylation N ur – PSA 42 2 A O log P 3.73

1/ . ± . . ± . N t 2 3 0 0 3h V 1 9 0 4 IMIDAFENACIN F 58% CL 7.6±1.6 Muscarinic antagonist N pb 88% Mwt 319.4 Metabolism: N-glucuronidation, H N 2 2 ur 8% PSA 56.0 A˚ dihydroxylation and oxidative O log P 2.42 degradation of imidazole

1/ t 2 6–8 h V 5.3 MILNACIPRAN F 85–90% CL 23 5-HT reuptake inhibitor, NH2 pb 13% Mwt 246.4 Antidepressant . ˚ 2 Metabolism: N-deethylation N O ur 50–60% PSA 46 3 A log P 0.83

(continued overleaf ) 238 46 Arylalkylamines

1/ ∗ O t 2 3–5 h V – INDECAINIDE NH2 F –CL–∗ H monkey N pb – Mwt 308.4 Antiarrhythmic 2 ur – PSA 55.1 A˚ Metabolite: N-desisopropyl log P 3.87

1/ N t 2 5.2 h V – VAMICAMIDE F –CL–Anticholinergic N pb – Mwt 297.4 H N 2 2 ur >80% PSA 59.2 A˚ O log P 1.45

1/ ± . ± . N t 2 6 1h V 0 6 0 2 DISOPYRAMIDE F 83±11% CL 1.2±0.4 N Antiarrhythmic pb 68–89% Mwt 339.5 Metabolite: N-desisopropyl H N 2 2 ur 55±6% PSA 59.2 A˚ O log P 2.33

1/ t 2 1.1–1.9 h V 1 ACTISOMIDE H F 0–43% CL 6.8±1.1 Antiarrhythmic N pb – Mwt 369.5 Metabolism: hydroxylation of N 2 N ur 26% PSA 35.9 A˚ piperidine, N-deisopropylation and log P 2.93 pyrrolidone formation O

1/ ± t 2 54 18 h V – DISOBUTAMIDE F –CL–Antiarrhythmic N N pb – Mwt 408.0 Metabolism: N-deisopropylation H N 2 2 Cl ur – PSA 49.6 A˚ O log P 4.31

1/ O t 2 12 h V 4.3 BIDISOMIDE F 43–62% CL 4 Antiarrhythmic N N pb – Mwt 408.0 Metabolism: piperidine H N . ˚ 2 hydroxylation, N-deisopropylation, 2 Cl ur 9% PSA 66 6 A log P 2.84 deacetylation and cyclization to O 2-pyrrolidone

1/ t 2 13–19 h V 2.6 DARIFENACIN F 15–19% CL 12 Muscarinic acetylcholine M N 3 O pb 98% Mwt 426.6 antagonist for treatment of urinary 2 H2N ur 3% PSA 55.6 A˚ incontinence O log P 4.50 Metabolism: hydroxylation and ring opening of dihydrobenzofuran, N-dealkylation of pyrrolidine 239

1/ EtO t 2 2–3 h V 3.8 DIPHENOXYLATE O F –CL–Opiate receptor agonist, pb 74–95% Mwt 452.6 antidiarrheal CN 2 N ur <1% PSA 53.3 A˚ Metabolism: ester hydrolysis, log P 4.51 aromatic hydroxylation (PhC-CN) Active metabolite: acid (difenoxin, 1/ t 2 4–12 h)

1/ t 2 8–10 h (iv) V 5–6 PIRITRAMIDE H2N O F – CL 6–9 Analgesic N pb 94% Mwt 430.6 Mostly administered iv CN 2 N ur Negligible PSA 73.4 A˚ log P 2.78

1/ O t 2 11–24 h V – BEZITRAMIDE F –CL–Analgesic O N pb – Mwt 492.6 Metabolism: hydrolytic removal of < . . ˚ 2 propionyl group N ur 0 3% PSA 67 7 A CN log P 4.16 N

1/ HO t 2 35–40 h V 1.1 LEVOCABASTINE O F 100% CL 0.43 Histamine H1 antagonist; duration pb 55% Mwt 420.5 of action: 20±4h NC 2 N ur 65–70% PSA 64.3 A˚ Metabolism: glucuronidation log P 4.05

1/ t 2 10–17 h V 0.3–0.6 ALVIMOPAN HO2C OH F 1–19% CL 6 Opiate antagonist; does not cross HN O pb 80–90% Mwt 424.5 bbb 2 ur 2% PSA 89.9 A˚ Metabolism: amide hydrolysis N log P 3.38

(continued overleaf ) 240 46 Arylalkylamines

1/ N t 2 16 h V 3 MARAVIROC N F 23–33% CL 11.3 Antiviral (HIV) N pb 76% Mwt 513.7 Metabolism: N-dealkylation of 2 N ur 8% PSA 63.1 A˚ tropane NH log P 5.30 F F O

t1/ 3 h (dog) V – CLOCAPRAMINE Cl O NH 2 2 F 16% CL – Antipsychotic pb – Mwt 481.1 Metabolite: mosapramine N 2 N N ur – PSA 52.8 A˚ log P 5.28

t1/ 15±2h V – MOSAPRAMINE Cl O 2 NH F 29±7% CL – Antipsychotic, metabolite of pb – Mwt 479.1 clocapramine N 2 N N ur – PSA 38.8 A˚ Metabolism: aromatic and benzylic log P 7.36 hydroxylation, oxidation to imidazolone

1/ t 2 5–9 h V 1TIAGABINE CO H 2 F 90% CL 3 GABA reuptake inhibitor, S pb 96% Mwt 375.6 antiepileptic . ˚ 2 N ur 2% PSA 97 0 A Metabolism (CYP3A4): log P 4.03 glucuronidation, thiophene S oxidation to 2-thiophenone

1/ F t 2 4h(pig) V – AMPEROZIDE F –CL–Mixed D2/5 –HT2 antagonist, O pb – Mwt 401.5 atypical antipsychotic 2 N N ur – PSA 35.6 A˚ Metabolism: N-deethylation H N log P 4.12

1/ ± / ± F t 2 111 57 h V F 28 18 PIMOZIDE H F 40–50% CL 4.1±3.8 O N Dopamine antagonist, pb 99% Mwt 461.6 antipsychotic N 2 ur <1% PSA 35.6 A˚ Metabolism: N-dealkylation of N log P 5.76 piperidine

F 241

1/ / F t 2 24 h V F –LIDOFLAZINE F –CL–Calcium channel blocker, pb – Mwt 491.6 vasodilator O 2 N ur – PSA 35.6 A˚ Metabolism: N-dealkylation N HN log P 5.42

1/ / F t 2 54–66 h V F – VANOXERINE F –CL–Dopamine reuptake inhibitor, pb >99% Mwt 450.6 antiarrhythmic, treatment of 2 N ur – PSA 15.7 A˚ cocaine addiction N log P 5.35 O

1/ F t 2 120–199 h V – PENFLURIDOL F –CL–Antipsychotic CF3 OH pb 98% Mwt 524.0 Metabolism: N-dealkylation of 2 Cl ur 5% PSA 23.5 A˚ piperidine to diarylbutyric acid N log P 6.95

1/ ± t 2 11 2h V – LOPERAMIDE O OH F 40% CL – Opioid agonist, antidiarrheal; does N Cl pb 95–97% Mwt 477.0 not cross bbb N 2 ur 1–2% PSA 43.8 A˚ Metabolism: N-demethylation, log P 4.15 N-oxidation

1/ ± ± t 2 18 5h V 18 7 HALOPERIDOL F 60±18% CL 12±3 Dopamine antagonist, OH pb 92±2% Mwt 375.9 antipsychotic; CYP2D6 inhibitor O Cl 2 ur 1% PSA 40.5 A˚ and inducer N log P 3.76 Metabolism: glucuronidation, N-dealkylation, dehydratation, and F oxidation to pyridine, reversible reduction of ketone to alcohol 1/ ± ± (t 2 67 51 h, CL 10 5)

1/ ± OH t 2 25 10 h V – BROMPERIDOL O Br F 50% CL – Antipsychotic N pb 90% Mwt 420.3 Metabolism: similar to haloperidol 2 ur <1% PSA 40.5 A˚ F log P 4.03

(continued overleaf ) 242 46 Arylalkylamines

1/ ± ± t 2 5 3h V 5 2 BENPERIDOL O H N F 45±20% CL 8±5 Antipsychotic N pb >90% Mwt 381.4 Metabolism: reversible reduction of O 2 ur 0.1% PSA 52.7 A˚ ketone to alcohol N log P 3.50

1/ ∗ . ± . H t 2 1.7–2.2 h V 1 4 0 3 DROPERIDOL O N F Low CL 13.9 ∗iv N pb 85–90% Mwt 379.4 Dopamine antagonist, O 2 ur 10%∗ PSA 52.7 A˚ antipsychotic N log P 3.10 Metabolism: N-dealkylation of tetrahydropyridine; withdrawn in F 2001

1/ ± t 2 13 5h V – PIPAMPERONE H2N O F –CL–Antipsychotic O N pb – Mwt 375.5 Metabolism: N-dealkylation of 2 N ur – PSA 66.6 A˚ piperidine, N-oxidation, reduction log P 2.47 of ketone F

t1/ 4±2h V 14 MELPERONE O 2 F 60% CL 46 Antipsychotic N pb – Mwt 263.4 CYP2D6 inhibitor 2 ur – PSA 20.3 A˚ F log P 3.76

1/ MeO O t 2 1.5–4.3 h V 1.2–1.6 BUFLOMEDIL F 30–80% CL 3.8–9.0 Vasodilator N pb 60–80% Mwt 307.4 Metabolism: 4-O-demethylation 2 ur 12–28% PSA 48.0 A˚ MeO OMe log P 3.13

1/ . ± . t 2 1 6 0 7h V – TOLPERISONE F 17–22% CL 36±9 Muscle relaxant N pb – Mwt 245.4 Metabolism: benzylic 2 O ur – PSA 20.3 A˚ hydroxylation, reduction of ketone log P 3.01 to alcohol

1/ t 2 1.6–1.8 h V – EPERISONE F Low CL – Muscle relaxant N pb – Mwt 259.4 Metabolism: benzylic hydroxylation 2 ur – PSA 20.3 A˚ O log P 4.34 243

1/ . ± . . ± . O t 2 3 7 0 4h V 4 0 0 4FENTANYL F 50% CL 13±2 Analgesic, narcotic N pb 84±2% Mwt 336.5 Metabolism: N-dealkylation of 2 ur 6–8% PSA 23.6 A˚ piperidine, amide hydrolysis N log P 3.68

1/ H t 2 14–16 h V 3.0 FENSPIRIDE N F 90% CL 2.6 Bronchodilator O pb – Mwt 260.3 Metabolism: aromatic O . ˚ 2 hydroxylation N ur – PSA 41 6 A log P 0.89

1/ . ± . . ± . O t 2 1 6 0 2h V 0 8 0 3ALFENTANIL F 42±15% CL 6.7±2.4 Analgesic N pb 92±2% Mwt 416.5 Metabolism: N-dealkylation of O < . ˚ 2 N ur 1% PSA 81 1 A piperidine and aniline N N OMe log P 2.16 N N

1/ O t 2 2h V 0.46 TREFENTANIL Ph F –CL5.6Analgesic N pb – Mwt 466.6 O 2 . ˚ N ur – PSA 71 8 A N F N log P 3.30 N N

1/ O t 2 3–10 min V 0.3–0.6 REMIFENTANIL F – CL 36–54 Opioid agonist, anesthetic for iv N pb 70% Mwt 376.5 dosing 2 ur Negligible PSA 76.2 A˚ Metabolite: carboxylic acid (t1/ 2h) N 2 MeO2C log P 2.05 CO2Me

1/ . ± . . ± . O t 2 2 7 1 2h V 1 7 0 6SUFENTANYL F 90% CL 12.7±2.5 Analgesic N pb 93±1% Mwt 386.6 Metabolism: N-dealkylation of 2 ur 6% PSA 61.0 A˚ piperidine and aniline, S N OMe log P 3.95 O-demethylation, aromatic hydroxylation

(continued overleaf ) 244 46 Arylalkylamines

1/ t 2 4–12 h V 5–8 INDORAMIN H F 24–31% CL 18–26 N Antihypertensive pb 72–92% Mwt 347.5 Active metabolite: 6-hydroxylated 2 N O ur <11% PSA 48.1 A˚ indole log P 2.87 N H

1/ t 2 7–16 h V 3–6 DOMPERIDONE H F 12–24% CL 7–10 Dopamine antagonist, antiemetic, O N pb 91–93% Mwt 425.9 does not cross bbb readily N . ˚ 2 Metabolism: aromatic Cl ur 1.4% PSA 67 9 A HN N N log P 4.05 5-hydroxylation at nonchlorinated arene, oxidative cleavage to O 1H-piperidine and 3-substituted propionic acid

1/ O t 2 6–14 h V 5–10 KETANSERIN F 53% CL 6–10 Serotonin antagonist, O pb 94% Mwt 395.4 antihypertensive N 2 N F ur <4% PSA 69.7 A˚ Metabolism: reversible reduction of log P 3.56 ketone, N-dealkylation of N O H piperidine, aromatic hydroxylation of quinazolinedione

t1/ 3.2±0.8h V 1.1±0.2 RISPERIDONE N O 2 F 66±28% CL 5.4±1.4 Antipsychotic, CYP2D6 substrate O pb 89% Mwt 410.5 F Metabolism: hydroxylation to N ± . 2 N ur 3 2% PSA 61 9 A˚ paliperidone (see below) log P 2.68 N

t1/ 20±3h V 7.5 PALIPERIDONE N O 2 F 28% CL – Active metabolite of risperidone O pb 74–77% Mwt 426.5 Metabolism: N-dealkylation, N−O F N 2 N ur 51–67% PSA 82.2 A˚ bond cleavage, oxidation to ketone, log P 1.52 aliphatic hydroxylation N OH

1/ ± t 2 6 3h V 1.5–2.3 ZIPRASIDONE N S F 45±15% CL 11.7 Antipsychotic N pb >99% Mwt 412.9 Metabolism: reductive N–S bond 2 N ur <1% PSA 76.7 A˚ cleavage, then S-methylation, O log P 4.00 oxidation to sulfoxide, N Cl N-dealkylation of piperazine H 245

1/ / t 2 14.4 h V F 20 BIFEPRUNOX F 54% CL – 5-HT1A agonist, antipsychotic > N NH pb 99% Mwt 385.5 2 N O ur 2% PSA 44.8 A˚ O log P 3.39

1/ t 2 6–9 h V 0.4–0.6 LECOZOTAN F – CL 0.7–0.8 5-HT1A antagonist for treatment of O N O pb >99.5% Mwt 483.6 Alzheimer’s disease N O 2 N ur <1% PSA 81.9 A˚ Metabolism: N-dealkylation to log P 1.94 eltoprazine NC N

1/ t 2 6–9 h V – FLESINOXAN F –CL–Antidepressant O N O pb – Mwt 415.5 N O N . ˚ 2 H ur – PSA 74 3 A OH F log P 2.36

1/ ∗ . ∗∗ t 2 1.1 h V 2 6 PRELADENANT ∗ ∗∗ O F 4% CL 37 ∗monkey OMe pb – Mwt 503.6 ∗∗rat 2 N N ur – PSA 125 A˚ Adenosin A2A antagonist for N O log P 1.45 treatment of Alzheimer’s disease Metabolism: O-demethylation H N 2 N N N N N

1/ O t 2 67–83 h V 9–13 DONEPEZIL, E-2020 F 100% CL 1.8–2.2 Acetylcholinesterase inhibitor for pb 93–96% Mwt 379.5 treatment of Alzheimer’s disease N 2 OMe ur 10% PSA 38.8 A˚ Metabolism: O-dealkylation, log P 4.71 4-hydroxylation of phenyl, OMe N-debenzylation

t1/ 18–33 h V 20–43 ILOPERIDONE OMe N O 2 F 96% CL 12–26 Dopamine and serotonin O F pb 95% Mwt 426.5 antagonist, antipsychotic 2 N ur <1% PSA 64.8 A˚ Metabolism: reduction of ketone to O log P 3.81 alcohol, O-demethylation, hydroxylation (continued overleaf ) 246 46 Arylalkylamines

1/ t 2 7–10 h V 2.4 CISAPRIDE F 40–50% CL – Peristaltic stimulant MeO NH MeO 2 pb 98% Mwt 466.0 Metabolism: N-dealkylation of H O N . ˚ 2 piperidine, hydroxylation of Cl ur 1–3% PSA 86 1 A N O log P 2.83 phenoxy, cleavage of ﬂuorophenyl F ether, no amide hydrolysis; withdrawn in 2000 for causing cardiac arrhythmias

1/ ± t 2 18 10 h V – SABELUZOLE O N S F –CL5.1Nootropic pb 99% Mwt 415.5 Metabolism: 6-hydroxylation of N N 2 F HO ur <0.5% PSA 77.1 A˚ benzothiazole, glucuronidation log P 4.26

1/ t 2 15–24 h V 2.5–3.4 LUBELUZOLE F O N S F – CL 2.2–3.9 Neuroprotectant pb >99% Mwt 433.5 Metabolism: 6-hydroxylation of N N 2 F HO ur – PSA 77.1 A˚ benzothiazole, glucuronidation log P 4.69

1/ ∗ t 2 14 h V – U-101387 O O ∗ ∗ S F 76% CL – monkey NH 2 pb – Mwt 401.5 Dopamine D4 antagonist 2 N ur Negligible PSA 84.3 A˚ N log P 2.42

t1/ 85–102 h V 20 SERTINDOLE F 2 F 74% CL 3.6 Antipsychotic pb >99% Mwt 440.9 Metabolism: N-dealkylation of 2 ur <1% PSA 40.5 A˚ piperidine, dehydrogenation of N log P 3.67 imidazolinone

O N N HN Cl

1/ t 2 2h V – DAPIPRAZOLE F –CL–α-Adrenergic blocker, antiglaucoma N pb – Mwt 325.5 < . ˚ 2 N N ur 10% PSA 37 2 A log P 2.89 N N 247

1/ . ± . . ± . t 2 6 5 1 8h V 1 0 0 3 TRAZODONE F 75±30% CL 1.8±0.6 Antidepressant N O pb 93% Mwt 371.9 Metabolism: N-oxidation, N Cl 2 ur <1% PSA 42.4 A˚ hydroxylation, N-dealkylation to N N N log P 2.76 1-(3-chlorophenyl)piperazine 1/ (t 2 4–8 h)

1/ < t 2 22 h V – ETOPERIDONE F –CL–Antidepressant O N N Cl pb – Mwt 377.9 Metabolism: similar to metabolism . 2 N N N ur Negligible PSA 42 4 A˚ of nefazodone (see below) log P 2.74

1/ t 2 3–10 h V 0.22–0.87 NEFAZODONE PhO F 15–23% CL 7.5 Antidepressant pb 99% Mwt 470.0 Metabolism: 1-hydroxylation of O . ˚ 2 ethyl group (to secondary alcohol: N N Cl ur – PSA 51 6 A 1/ . log P 4.09 t 2 1 4–6.5 h), deethylation to N N N triazoledione, N-dealkylation of piperazine

1/ O t 2 75–146 h V 4.9 ARIPIPRAZOLE F 87% CL 0.7 Antidepressant, antipsychotic, NH pb 99% Mwt 448.4 crosses bbb 2 N Cl ur <1% PSA 44.8 A˚ Metabolism: dehydrogenation of N Cl O log P 5.60 piperidinone, N-dealkylation, N-oxidation

1/ / O t 2 9–21 h V F 2.8 CILOSTAZOL F 87–100% CL/F 3 PDE III inhibitor, antithrombotic NH pb 95–98% Mwt 369.5 Metabolites: 4-trans-hydroxy, 2 N N ur <1% PSA 81.9 A˚ 3,4-dehydro N log P 3.40 O N

t1/ 11–18 h V – ENSACULIN, ANSECULIN, OMe 2 F –CL–KA-672 O N pb High Mwt 452.6 Nootropic 2 N OMe ur – PSA 64.4 A˚ Metabolism: aromatic log P 4.29 hydroxylation O

1/ O t 2 10–26 h V 2 PICUMAST N F 57% CL 1.5 Antiallergic N Cl pb – Mwt 441.0 Metabolism: N-dealkylation, 2 O ur Negligible PSA 42.0 A˚ hydroxylation of 3-CH3, then oxidation to carboxylic acid O log P 4.13

(continued overleaf ) 248 46 Arylalkylamines

1/ t 2 1–2 h V – LEVODROPROPIZINE F 75% CL – Antiussive HO N pb 11–14% Mwt 236.3 Metabolism: aromatic 2 N ur – PSA 46.9 A˚ 4-hydroxylation HO log P −0.03

1/ . ± . t 2 5 4 3 2h V – NAFTOPIDIL F 7–30% CL 11±1.6 Antihypertensive O N pb 95–97% Mwt 392.5 Metabolism: aromatic 2 N OMe ur – PSA 45.2 A˚ hydroxylation, piperazine HO log P 4.1 dealkylation, O-demethylation

1/ t 2 2–5 h V 0.4–0.8 URAPIDIL F 63–80% CL 1.8–3.8 Antihypertensive N pb 75–80% Mwt 387.5 Metabolites: H 2 O N N OMe ur 10–15% PSA 68.4 A˚ 4-hydroxy-2-methoxyphenyl (inactive, t1/ 6–10 h), N-desmethyl NN log P 1.64 2 1/ (active, t 2 10–16 h) O

1/ . ± . F t 2 4 5 1 0h V – NIAPRAZINE F –CL–Histamine H1 antagonist N pb – Mwt 356.4 Metabolism: N-dealkylation, H 2 N N N ur – PSA 48.5 A˚ N-oxidation, N-dearylation, log P 2.16 aromatic hydroxylation O

t1/ 20–26 h V/F 11–17 VILAZODONE H2N 2 O F –CL/F 5.6–6.9 5-HT reuptake inhibitor, 5-HT1A pb 96–99% Mwt 441.5 agonist, antidepressant O 2 ur 0.2–1.0% PSA 102 A˚ Metabolism: hydroxylation to NC N log P 2.59 6-hydroxyindole, then N glucuronidation

N H

1/ t 2 5.5 h V – CARMOXIROLE

HO2C F –CL–Antihypertensive, dopamine DA2 pb – Mwt 374.5 agonist, does not cross bbb readily N 2 ur – PSA 56.3 A˚ Metabolite: glucuronide N log P 4.60 H

t1/ 5–10 h V 0.9 AVITRIPTAN N N 2 F 17% CL 6.4 Antimigraine, 5-HT1-receptor N N pb – Mwt 458.6 agonist N OMe 2 ur 2–4% PSA 112A˚ Active metabolites: N-desmethyl 1/ 1/ . H2N log P 1.58 (t 2 11 h), O-desmethyl (t 2 5 2h) S O O 249

1/ N t 2 1–3 h V – IPSAPIRONE F 10% (dog) CL – Anxiolytic O N N pb – Mwt 401.5 Metabolism: N-dealkylation of N . 2 N ur – PSA 95 1 A˚ piperazine S O log P 0.97 O

1/ ∗ t 2 0.8–1.8 h V 0.2 REPINOTAN O H F –CL2.2∗iv N N O pb – Mwt 400.5 5-HT1A agonist, neuroprotectant, 2 S O ur – PSA 84.1 A˚ crosses bbb O log P 2.85 Metabolism: chroman 6-hydroxylation

1/ N t 2 1.2–1.4 h V – TANDOSPIRONE F Low CL – Anxiolytic, antidepressant O N N pb – Mwt 383.5 Metabolism: hydroxylation of H N . ˚ 2 pyrimidine and norbornane, N ur – PSA 69 6 A log P 1.09 N-dealkylation of piperazine O H

t1/ 12–18 h V 95 LURASIDONE N S 2 H O F 9–19% CL 60 Antipsychotic N pb >99% Mwt 492.7 Metabolism: N-dealkylation, N N 2 H ur 0.1% PSA 85.0 A˚ hydroxylation of norbornane, O log P 4.52 S-oxidation

1/ . ± . N t 2 2–11 h V 5 3 2 6 BUSPIRONE F 4% CL 28–45 Anxiolytic O N N pb 95% Mwt 385.5 Metabolism: hydroxylation of N 2 α N ur <1% PSA 69.6 A˚ pyrimidine at position 5 and to log P 1.59 the carbonyl groups, N-dealkylation O of piperazine

1/ ± N t 2 3 2h V 4.8 GEPIRONE F 15% CL – Anxiolytic O N N pb – Mwt 359.5 Metabolism: as buspirone N . 2 N ur – PSA 69 6 A˚ log P 1.06 O

1/ N t 2 1–6 h V – LESOPITRON F 10% (dog) CL – Anxiolytic N N pb – Mwt 320.8 Metabolism: pyrimidine N . ˚ 2 N ur – PSA 45 2 A 5-hydroxylation Cl N log P 2.68

(continued overleaf ) 250 46 Arylalkylamines

1/ t 2 2–7 h V – PIRIBEDIL N F 10% CL – Dopamine agonist, vasodilator pb – Mwt 298.3 Metabolism: acetal hydrolysis to O 2 N N ur 0% PSA 50.7 A˚ catechol, pyrimidine hydroxylation O N log P 2.43 to 4-hydroxypyrimidine, N-oxidation of pyrimidine

1/ ± t 2 11 4h V – BLONANSERIN F –CL–5-HT2A/D2 antagonist, atypical pb >99.7% Mwt 367.5 antipsychotic 2 N ur 0% PSA 19.4 A˚ Metabolism: hydroxylation at (CH ) CH (CH ) N log P 6.03 2 2 2 2 2 N F

1/ ± t 2 6 2h V – 1-(2-PYRIMIDINYL)PIPERAZINE N F –CL–Active metabolite of ipsapirone, N N pb – Mwt 164.2 gepirone, tandospirone, buspirone 2 HN ur – PSA 41.1 A˚ log P 0.49

1/ F t 2 6–8 h V – 1-(4-FLUOROPHENYL) F –CL–PIPERAZINE pb – Mwt 180.2 Active metabolite of niaprazine N 2 ur – PSA 15.3 A˚ HN log P 1.44

1/ t 2 3–6 h V 2.5 1-(3-CHLOROPHENYL) F 12–84% CL 6.1 PIPERAZINE pb – Mwt 196.7 Recreational drug, causes . 2 N Cl ur – PSA 15 3 A˚ headaches Metabolism: aromatic HN log P 1.74 hydroxylation, oxidative degradation of piperazine

1/ t 2 7–9 h V 3.5 ELTOPRAZINE F 100% CL 8 5-HT1/2C agonist, serenic N O pb 15% Mwt 220.3 2 HN O ur 40% PSA 33.7 A˚ log P 0.86

1/ t 2 variable V – PIPERAZINE F 75% CL – Anthelmintic NH pb 60–70% Mwt 86.1 Metabolites: N-nitroso, HN 2 ur 20% PSA 24.1 A˚ N-nitroso-3-hydroxy log P −1.50 251

1/ O t 2 1.9–3.5 h V 6 METHYLPHENIDATE MeO F 11–52% CL 0.78–4.8 CNS stimulant, crosses bbb pb 10–33% Mwt 233.3 Metabolism: ester hydrolysis to 2 ur <1% PSA 38.3 A˚ ritalinic acid, oxidation to lactam NH log P 2.31

1/ . ± . t 2 3–5 h V 4 4 0 9 MEPERIDINE, PETHIDINE EtO F 50–60% CL 17±5 Analgesic, narcotic; O pb 65–75% Mwt 247.33 Metabolism: N-demethylation (to 2 1/ ur 1–25% PSA 29.5 A˚ normeperidine, t 2 14–21 h), N log P 2.19 hydrolyis of ester, aromatic 4-hydroxylation

1/ t 2 7–27 h V – FEMOXETINE F 5–10% CL – Antidepressant (SRI); high pb – Mwt 311.4 ﬁrst-pass effect 2 N O ur <2% PSA 21.7 A˚ Metabolism: N- and log P 3.89 O-demethylation, aromatic hydroxylation OMe

1/ ± ± F t 2 17 3h V 17 10 PAROXETINE F 50% CL/F 8.6±3.2 Antidepressant; CYP2D6 substrate pb 95% Mwt 329.4 and inhibitor 2 ur <2% PSA 39.7 A˚ Metabolism: O-demethylenation, HN O O log P 3.70 then O-methylation (COMT), O-dearylation to O hydroxymethylpiperidine

1/ ∗ t 2 24 h V 46 BRASOFENSINE Cl ∗ ∗ F 0.8% CL 32 ∗monkey pb – Mwt 327.3 Dopamine reuptake inhibitor for Cl 2 ur 0% PSA 24.8 A˚ treatment of Parkinson’s disease N N OMe log P 3.15 Metabolism: E to Z isomerization of oxime, N- and O-demethylation

1/ Cl t 2 8d V 8.6 TESOFENSINE F >90% CL 0.5–0.6 Monoamine reuptake inhibitor; pb – Mwt 328.3 appetite suppressant Cl 2 ur – PSA 12.5 A˚ Active metabolite: N-desmethyl N O 1/ log P 3.94 (t 2 14 d)

(continued overleaf ) 252 46 Arylalkylamines

t1/ 5.2 h (iv) V 1.5 FLAVOPIRIDOL HO OH 2 HO F 20% (rat) CL 6.1 Antineoplastic O pb 94% Mwt 401.8 Metabolism: glucuronidation 2 ur – PSA 90.2 A˚ N O log P 1.93 Cl

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; COMT, catechol-O-methyltransferase; GABA, γ-aminobutyric acid; 5-HT, 5-hydroxytryptamine; PDE, phosphodiesterase; sc, subcutaneous.

Table 46.2 (Arylalkyl)piperazines and -piperidines. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

t1/ 6h V 4.6 TRIMETAZIDINE OMe 2 F 89% CL 0.9 Antianginal MeO OMe NH pb 16% Mwt 266.3 Metabolism: O-demethylation 2 N ur 62% PSA 43.0 A˚ log P −0.19

t1/ 7–24 h V 16±3CYCLIZINE N 2 F 75% CL 0.2 Antiemetic N pb 60% Mwt 266.4 Duration of action: 5±1h 2 ur <1% PSA 6.48 A˚ Metabolism: N-demethylation to 1/ log P 2.47 inactive norcyclizine (t 2 20 h, pb 59%)

1/ Cl t 2 12 h V – CHLORCYCLIZINE N F –CL–Histamine H1 antagonist N pb – Mwt 300.8 Metabolism: N-demethylation to 2 ur – PSA 6.48 A˚ norchlorcyclizine 1/ log P 3.24 (t 2 6–9 d, pb 88%)

1/ Cl t 2 6h V – MECLIZINE, MECLOZINE N F 22% (dog) CL – Histamine H1 antagonist, N pb – Mwt 391.0 antiemetic 2 ur – PSA 6.48 A˚ Metabolism: N-debenzylation log P 5.28 253

1/ ± t 2 5 2h V – CINNARIZINE N F 75–100% CL – Histamine H1 antagonist, N pb 91% Mwt 368.5 antiemetic 2 ur <1% PSA 6.48 A˚ Metabolism: aromatic log P 5.03 4-hydroxylation, N-oxidation, piperazine dealkylation

1/ F t 2 17–19 d V 43–78 FLUNARIZINE N F 85% CL 6.8 Ca channel blocker, antimigraine N pb 90% Mwt 404.5 Metabolism: aromatic 2 ur <0.2% PSA 6.48 A˚ 4-hydroxylation (cinnamyl group), log P 5.59 N-oxidation, piperazine dealkylation

t1/ 55±16 d V 15 ALMITRINE HN 2 F 70% CL 4±2 Respiratory stimulant N N pb 99.5% Mwt 477.6 Metabolism: dihydroxylation of 2 F ur – PSA 69.2 A˚ vinyl groups, deallylation N N N H log P 6.11 N

1/ O t 2 42–56 h V – INCB 9471 F >95% CL – CC chemokine receptor 5 (CCR5) N N pb 84% Mwt 559.7 antagonist, antiviral (HIV) 2 N N ur – PSA 61.8 A˚ Metabolism: O-deethylation F C 3 N log P 3.45

1/ t 2 28–33 h V 12 VICRIVIROC ∗ ∗ O F 89–100% CL 5.4 monkey pb 84% Mwt 533.6 CCR5 antagonist, antiviral (HIV) N N 2 ur 4% PSA 61.8 A˚ Metabolism: N-oxidation of F C 3 N N log P 2.00 pyrimidine, conversion of N pyrimidine to pyrazole-N-oxide, O-demethylation, ring opening of OMe piperazine by N-dealkylation, benzylic C−N bond cleavage, oxidation of CH2OMe to CO2H (continued overleaf ) 254 46 Arylalkylamines

1/ ± ± t 2 17 3h V 37 4 OXATOMIDE O F – CL – Histamine H1 antagonist, pb 91–98% Mwt 426.6 antiemetic N N 2 NH ur <0.1% PSA 38.8 A˚ Metabolism: N-dealkylation, N log P 4.34 aromatic hydroxylation of benzimidazolone

1/ ± Cl O t 2 7–20 h V 16 3 HYDROXYZINE N OH F –CL13±4 Histamine H1 antagonist, N pb 93% Mwt 374.9 antipruritic 2 ur 0.8% PSA 35.9 A˚ Main metabolite: cetirizine (see log P 2.32 below)

1/ ± Cl O CO H t 2 9 2h V 0.5–0.8 CETIRIZINE N 2 F 60–70% CL 0.6–1.2 Histamine H1 antagonist, N pb 93% Mwt 388.9 antipruritic 2 ur 65±5% PSA 53.0 A˚ Duration of action: 18±6h log P 1.62 Metabolism: O-dealkylation

1/ t 2 25 h (iv) V 268–350 ZOSUQUIDAR N O F – CL 108–158 P-Glycoprotein inhibitor, adjunct N HO pb – Mwt 527.6 antineoplastic 2 ur – PSA 48.8 A˚ Metabolism: N-oxidation and F N log P 4.30 hydroxylation of quinoline F

1/ t 2 1–4 h V – CYPROHEPTADINE N F –CL–Histamine H1 antagonist, pb 96–99% Mwt 287.4 antipruritic 2 ur 0% PSA 3.2 A˚ Metabolites: quaternary log P 5.1 glucuronide, N-desmethyl, epoxide

1/ t 2 9–12 h V – AZATADINE N F –CL–Histamine H1 antagonist, pb Low Mwt 290.4 antipruritic 2 ur 20% PSA 16.1 A˚ N log P 3.5 255

1/ t 2 23 h V – PIZOTYLINE, PIZOTIFEN N F 78% CL – 5-HT antagonist for migraine pb 91% Mwt 295.4 prophylaxis 2 ur <1% PSA 31.5 A˚ Main metabolite: N-glucuronide 1/ −1) log P 2.71 (t 2 23 h, V 1lkg S

1/ ± t 2 18 7h V 56 KETOTIFEN ∗ F 50% CL – 10% of N-desmethyl metabolite; N pb 75% Mwt 309.4 histamine H1 antagonist, 2 ur 1%∗ PSA 48.6 A˚ antipruritic log P 2.19 Metabolism: N-demethylation, N-oxidation, N-glucuronidation, O S reduction of keto group Active metabolite: desmethyl

1/ ± Cl t 2 18 6h V 49 DESLORATADINE F High CL – NH Metabolite of loratadine (see below) pb 73–87% Mwt 310.8 Metabolism: 3-hydroxylation of 2 ur 0% PSA 24.9 A˚ pyridine, then glucuronidation N log P 3.5

1/ ± ± O t 2 8 6h V 120 80 LORATADINE Cl F – CL 142±57 Histamine H1 antagonist N O pb 97% Mwt 382.9 Duration of action: 24 h 2 ur – PSA 42.4 A˚ Metabolism: hydrolysis of log P 4.6 carbamate to desloratadine N

1/ Cl t 2 6h V 143 RUPATADINE F 50% CL – Histamine H antagonist, N 1 pb >95% Mwt 416.0 antipruritic 2 N ur 0% PSA 29.0 A˚ Metabolism: piperidine N log P 6.11 N-dealkylation to desloratadine, then 3-hydroxylation of pyridine to 3-hydroxydesloratadine

1/ O t 2 4–11 h V – LONAFARNIB Cl F 30–70% CL/F 3–6 Farnesyltransferase inhibitor, Br N pb – Mwt 638.8 antineoplastic 2 ur <0.02% PSA 79.5 A˚ Metabolism: hydroxylation at log P 5.03 CH2NCONH2, then elimination of N N H2O

O NH2 Br

(continued overleaf ) 256 46 Arylalkylamines

1/ ± N S t 2 43 13 h V – RITANSERIN F 75–83% CL – 5-HT2 antagonist, anxiolytic, F N N pb >98% Mwt 477.6 antidepressant 2 O ur – PSA 61.2 A˚ log P 5.20

1/ t 2 – V – TERFENADINE ∗ F <1% CL 1133 Nonsedating histamine H1 pb 97% Mwt 471.7 antagonist, prodrug of fexofenadine 2 ur Negligible PSA 43.7 A˚ (see below) N ∗fexofenadine on oral dosing of OH log P 5.62 Ph OH terfenadine: 70% Other metabolism: N-dealkylation Ph of piperidine; withdrawn in 1998 for causing cardiac arrhythmias

1/ ± CO2H t 2 12 5h V 5.4–5.8 FEXOFENADINE F 33% CL/F 9±2 Nonsedating histamine H1 pb 60–70% Mwt 501.7 antagonist, P-gp substrate, 2 N ur 19±7% PSA 81.0 A˚ metabolite of terfenadine (see OH Ph OH log P 3.73 above)

1/ t 2 6–20 h V –EBASTINE F –CL–Histamine H1 antagonist pb 98% Mwt 469.7 Metabolism: hydroxylation of . ˚ 2 tert-butyl, N-dealkylation of Ph N ur 1.3–1.8% PSA 29 5 A piperidine O log P 6.81 Ph O Main active metabolite: carebastine (see below)

1/ ± CO2H t 2 17 10 h V 1.4–2.2 CAREBASTINE F – CL 14–15 Metabolite of ebastine pb 98% Mwt 499.6 2 Ph N ur 85±10% PSA 66.8 A˚ O Ph O log P 4.93

1/ CO2H t 2 5–14 h V 0.5 BILASTINE ∗ F 25–69% CL 4.6 ∗animals pb 85% Mwt 463.6 Histamine H1 antagonist; no 2 N ur 33% PSA 62.7 A˚ metabolism in humans N log P 5.06 N O 257

1/ t 2 2.3–3.3 h V – BEPOTASTINE F >80% CL – Nonsedating histamine H1 N N CO H pb 55% Mwt 388.9 antagonist 2 2 ur >70% PSA 62.7 A˚ Metabolism: piperidine O log P 3.67 N-dealkylation, oxidative Cl degradation of side chain, ether cleavage to benzylic alcohol

1/ ± t 2 32 8h V – DIPHENYLPYRALINE F –CL–Histamine H1 antagonist N pb >99% Mwt 281.4 Metabolites: N-oxide, N-desmethyl 2 ur 2–7% PSA 12.5 A˚ O log P 3.43

1/ ∗ H t 2 3h V – PRAMIVERINE N F –CL–∗monkey pb 90% Mwt 293.5 Antispasmodic 2 ur Low PSA 12.0 A˚ Metabolism: N-dealkylation, log P 5.53 hydroxylation

1/ t 2 31 h V 2.7 BUDIPINE F 47% CL – Antiparkinsonian N pb 96% Mwt 293.5 Metabolites: 4-hydroxyphenyl 2 1/ ur 20% PSA 3.24 A˚ (t 2 59 h), N-oxide, alcohol log P 4.98 (hydroxylation of tert-butyl)

1/ ± . ± . t 2 8 2h V 6 4 2 4 LORCAINIDE ∗ ∗ Cl F 1–65% CL 17.5±2.8 dose dependent N pb 80±5% Mwt 370.9 Antiarrhythmic 2 N ur <2% PSA 23.6 A˚ Active metabolite: N-desisopropyl 1/ ± Ph log P 3.62 (t 2 27 8h) O

1/ t 2 55 h V – PIMAVANSERIN, ACP-103 N > F 43% (rat) CL 5.9–8.5 5-HT2a inverse agonist N pb 95% Mwt 427.6 2 ur – PSA 44.8 A˚ F HN O log P 4.67

(continued overleaf ) 258 46 Arylalkylamines

1/ ± t 2 22 4h V 14.5 AZELASTINE ± N F 82% CL 9 3 Histamine H1 antagonist N ± N pb 83 5% Mwt 381.9 Metabolites: 6-hydroxy (para to 2 ur 2–7% PSA 35.9 A˚ carbonyl group), N-desmethyl 1/ ± Cl O log P 3.47 (t 2 54 15 h)

1/ t 2 3–7 h V –EMEDASTINE O N F 46–90% CL 21 Histamine H1 antagonist; eye drops N N pb – Mwt 302.4 Metabolism: aromatic 5- and 2 N ur 3.6% PSA 33.5 A˚ 6-hydroxylation, N-oxidation of log P 2.78 diazepane

1/ t 2 9–28 h V – NOBERASTINE H F –CL–Histamine H1 antagonist O N N pb – Mwt 311.4 N 2 N NH ur – PSA 67.9 A˚ log P 1.18

1/ t 2 5–18 h (iv) V 1.5–8.4 SNS-032 N O O S F 4–33% CL – Cyclin-dependent kinase inhibitor, S N pb – Mwt 380.5 antineoplastic H 2 N NH ur – PSA 134 A˚ log P 2.79

1/ F t 2 8–13 h V 1.0–1.4 MIZOLASTINE F 58±8% CL 1.2 Nonsedating histamine H1 N N pb 98% Mwt 432.5 antagonist 2 ur <0.5% PSA 65.8 A˚ Metabolism: glucuronidation, N N HN log P 3.63 sulfation N O

1/ / t 2 1–2 d V F 250 ASTEMIZOLE F 95% CL 11 Nonsedating histamine H F N 1 OMe pb 97% Mwt 458.6 antagonist, does not cross bbb 2 ur 0% PSA 42.3 A˚ Active metabolite: O-desmethyl 1/ log P 5.52 (t 2 7–20 d); withdrawn in 1999 N NH because of afﬁnity to hERG N

t1/ 5–7 h V 2.4 NARATRIPTAN N 2 F 63–74% CL 6.6 Antimigraine, 5-HT1A,B,D,F agonist HN S O pb 20–31% Mwt 335.5 Metabolite: N-oxide 2 O ur 50% PSA 73.6 A˚ N log P 1.35 H 259

t1/ 12–15 h V 4.3–6.0 BROFAROMINE NH 2 F 90% CL 4.3–4.8 Antidepressant, MAO inhibitor pb 98% Mwt 310.2 Metabolism: O-demethylation 2 O ur <1% PSA 34.4 A˚ MeO log P 3.65 Br

t1/ 10 h V – INDALPINE NH 2 F –CL–Antidepressant (SSRI) pb – Mwt 228.3 Metabolism: oxidation to 2 ur 3% PSA 27.8 A˚ 2-piperidinone (t1/ 12 h) N 2 H log P 3.27

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; hERG, human ether-a-go-go-related` gene; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor.

Table 46.3 Aryloxyalkylamines. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 2.3–2.7 h V 0.21–0.24 GALLAMINE F – CL 1.2–1.6 Muscle relaxant N O N pb 30–70% Mwt 423.6 2 O ur 85–100% PSA 37.4 A˚ log P 2.58 N O

1/ ± . ± . t 2 9 2h V 4 9 0 5 MEXILETINE F 87±13% CL 6±3 Antiarrhythmic NH2 pb 63±3% Mwt 179.3 Metabolism: aromatic O 2 ur 4–15% PSA 12.7 A˚ 4-hydroxylation, benzylic log P 2.6 hydroxylation, glucuronidation

t1/ – V – POZANICLINE N 2 F –CL–Nicotinic acetylcholine agonist, H N pb – Mwt 192.3 nootropic, neuroprotective O 2 ur – PSA 34.2 A˚ log P 1.41

1/ ± ± t 2 2 1h V 14 6 MEDIFOXAMINE F 21% CL 18±3 Antidepressant pb – Mwt 257.3 Metabolism: N-demethylation, 2 O ur 0.3% PSA 21.7 A˚ N-oxidation, oxidation to N diphenoxyacetic acid O log P 2.52

(continued overleaf ) 260 46 Arylalkylamines

1/ t 2 3.3 h V 8 BIFEMELANE F 48% CL – Nootropic pb 95% Mwt 269.4 2 ur <1% PSA 21.3 A˚ log P 4.19 O N H

1/ t 2 4–5 h V – BENPROPERINE F 92% CL – Antiussive pb – Mwt 309.5 Metabolites: 4-piperidinol, 2 ur – PSA 12.5 A˚ 3-piperidinol log P 5.15 N O

1/ HO C t 2 9h V – DG-051 2 F >80%∗ CL – ∗ O monkey pb – Mwt 389.9 Leukotriene A4 hydrolase inhibitor 2 ur – PSA 59.0 A˚ Metabolism: N-oxidation, aromatic Cl O N log P 4.63 hydroxylation (ortho to Cl)

1/ O t 2 7–9 h V – TRIMETHOBENZAMIDE MeO F 56–62% CL – Dopamine antagonist, antiemetic N H pb – Mwt 388.5 Metabolite: N-oxide N 2 MeO O ur 30–50% PSA 69.3 A˚ OMe log P 1.26

1/ MeO t 2 30–50 h V – ARZOXIFENE F 5%∗ CL – ∗monkey pb – Mwt 475.6 Estrogen receptor modulator for 2 ur – PSA 79.4 A˚ treatment of osteoporosis O log P 7.78 Metabolism: glucuronidation, S N O-demethylation; development O discontinued

1/ HO t 2 28 h V – RALOXIFENE F 2% CL – Antiosteoporotic pb 99% Mwt 473.6 Metabolism: glucuronidation 2 O ur – PSA 98.2 A˚ log P 4.57 S N O

HO 261

1/ ± ± HO t 2 28 11 h V 15 4 BAZEDOXIFENE F 6% CL 6 Estrogen receptor modulator for pb 96–99% Mwt 470.6 treatment of osteoporosis 2 ur <1% PSA 52.9 A˚ Metabolism: glucuronidation log P 6.59 N N O

1/ ± ± O t 2 25 12 d V 66 44 AMIODARONE ± . ± . I F 46 22% CL 1 9 0 4 Antiarrhythmic, antithyroid 1/ O pb 100% Mwt 645.3 Metabolites: N-desethyl (t 2 61 d), N 2 O ur 0% PSA 42.7 A˚ iodide I log P 7.82

1/ O t 2 7h V 13 BUDIODARONE O F –CL–Antiarrhythmic O I pb – Mwt 703.4 Metabolism: ester hydrolysis 2 O ur – PSA 69.0 A˚ N O log P 8.00 I

1/ O t 2 24–30 h V 19–22 DRONEDARONE F 15–20% CL – Antiarrhythmic > O pb 98% Mwt 556.8 Main metabolite: N-desbutyl 2 1/ O N ur 0% PSA 97.2 A˚ (t 2 20–25 h) O O log P 7.58 N S H

1/ O t 2 – V – MORCLOFONE F 80% CL – OMe Cough suppressant O pb 99% Mwt 405.9 N . ˚ 2 Cl O ur – PSA 57 2 A OMe log P 2.55

1/ t 2 2–3 h V 3.4 TIROPRAMIDE H F 23% CL 3.3–4.8 N Antispasmodic pb 65% Mwt 467.6 Metabolism: N-deethylation, O N 2 N O O ur – PSA 61.9 A˚ N-depropylation log P 4.14

(continued overleaf ) 262 46 Arylalkylamines

1/ OMe t 2 14–17 h V 7–10 SATAVAPTAN, SR 121463 O O O F 6–11% CL 13–17 Vasopressin antagonist; S O pb 95–96% Mwt 643.8 discontinued because of low F HN N 2 ur <3% PSA 132 A˚ (high ﬁrst-pass metabolism). O N log P 4.77 O EtO

1/ ± . ∗ t 2 91 56 h V 6 5 MOFAROTENE F 60%∗ CL/F 8±4 ∗dog pb – Mwt 433.6 Arotinoid for cancer prevention 2 ur – PSA 21.7 A˚ log P 6.76 O N O

1/ t 2 7d V 22 CENTCHROMAN, OMe ∗ F 60% CL 1.6 ORMELOXIFEN pb 90–100% Mwt 457.6 ∗rat 2 ur – PSA 30.9 A˚ Estrogen receptor modulator, O log P 6.21 contraceptive Metabolism: O-demethylation N O

1/ OH t 2 6d V 13 LASOFOXIFENE F 60% CL 1 Estrogen receptor modulator for pb >99% Mwt 413.6 treatment of osteoporosis 2 ur <2% PSA 32.7 A˚ Metabolism: sulfation, log P 6.51 glucuronidation, oxidation of pyrrolidine, catechol formation N followed by O-methylation O

1/ > t 2 5–7 d V 60 CLOMIPHENE F >90% CL – Mixture of isomers; enclomiphene pb – Mwt 406.0 shown; gonad-stimulating principle 2 Cl ur – PSA 12.5 A˚ Metabolism: N-deethylation, log P 5.85 aromatic 4-hydroxylation N O 263

1/ ± / ± t 2 8 4d V F 55 5 TAMOXIFEN F 25–100% CL/F 1.4 Antiestrogen, antineoplastic pb >98% Mwt 371.5 Metabolites: 4-hydroxyphenyl 2 ur <1% PSA 12.5 A˚ (vicinal to ethyl group), N log P 5.13 N-desmethyl O

1/ HO t 2 1–2 d V 7 DROLOXIFENE F 80% CL 32±4 Antineoplastic pb – Mwt 387.5 Metabolites: glucuronide, 2 ur <1% PSA 32.7 A˚ N-desmethyl, N-oxide log P 7.30 N O

1/ t 2 4–7 d V 7–10 TOREMIFENE F 100% CL 1 Antineoplastic pb 99.7% Mwt 406.0 Metabolites: 4-hydroxy, Cl 2 ur – PSA 12.5 A˚ N-desmethyl N log P 4.77 O

1/ t 2 30 h V – OSPEMIFENE F –CL–Metabolite of toremifene; treatment pb 93–98% Mwt 378.9 of postmenopausal osteoporosis 2 Cl ur – PSA 29.5 A˚ and urogenital atrophy OH log P 4.43 O

Table 46.4 Piperidines and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

t1/ 1–5 h V – LOBELINE O OH 2 F Low CL – Respiratory stimulant N pb – Mwt 337.5 2 ur <0.5% PSA 40.5 A˚ log P 3.61

1/ t 2 8–13 h V 1 TEDISAMIL F 50% CL 3–4 Potassium channel blocker, N pb 96% Mwt 288.5 bradycardic, antiarrhythmic 2 ur 84% (iv) PSA 6.48 A˚ Metabolism: hydroxylation N log P 3.67

(continued overleaf ) 264 46 Arylalkylamines

1/ t 2 3h V 2–5 TALSACLIDINE O F 90% CL – Muscarinic agonist pb – Mwt 165.2 > . ˚ 2 N ur 86% PSA 12 5 A log P 0.92

t1/ 3–6 h V 6 CEVIMELINE S 2 F –CL–Muscarinic agonist, < O pb 20% Mwt 199.3 parasympathomimetic 2 ur 16% PSA 37.8 A˚ Metabolism: glucuronidation, N log P 2.44 oxidation to sulfoxide, N-oxide

1/ t 2 0.2 h V 2.6 ARECOLINE F Low CL 170 Anthelmintic, cathartic CO2Me N pb – Mwt 155.2 Metabolism: N-oxidation, 2 ur 0.3–0.4% PSA 29.5 A˚ hydrogenation of alkene, ester log P −0.20 hydrolysis, then conjugation with glycine

1/ t 2 1.5–2.0 h V – GABOXADOL O F 84–93% CL 6.9 Hypnotic pb <2% Mwt 140.1 Metabolism: O-glucuronidation NH 2 . ˚ HN O ur 50–60% PSA 50 4 A log P 0.71

1/ S t 2 3.6 h V – XANOMELINE N < N F 1% CL – Muscarinic agonist, crosses bbb; pb – Mwt 281.4 cholinergic, nootropic N 2 O ur – PSA 66.5 A˚ Metabolites: N-oxide, N-desmethyl log P 4.28

1/ t 2 7–51 h V 6.2 PHENCYCLIDINE F 50–90% CL 5.4 Anesthetic, hallucinogenic pb 60–70% Mwt 243.4 Metabolism: piperidine 2 N ur 9–10% PSA 3.24 A˚ 4-hydroxylation, cyclohexane log P 4.25 hydroxylation, piperidine ring opening by N-dealkylation

1/ t 2 12–16 h V – SILPERISONE Si N F –CL–Muscle relaxant, crosses bbb pb 86–95% Mwt 265.4 2 F ur – PSA 3.24 A˚ log P 4.51

1/ t 2 7–8 h V 3.2 ROXATIDINE OH > H F 95% CL 5–7 Histamine H2 antagonist; N O N pb 5–7% Mwt 306.4 roxatidine is dosed as the acetate 2 O ur 55–60% PSA 61.8 A˚ ester prodrug log P 1.77 265

1/ t 2 13–33 h V – TICLOPIDINE Cl F 80–90% CL – Antithrombotic pb 98% Mwt 263.8 Metabolism: oxidation to N 2 ur 2% PSA 31.5 A˚ 2-hydroxythiophene, S-oxidation, S log P 3.23 then dimerization; may lead to neutro- and thrombocytopenia

1/ ∗ t 2 2.5 h V – CLOPIDOGREL F –CL–∗acid: 8 h Cl CO Me 2 pb 98% Mwt 321.8 Platelet inhibitor, antithrombotic 2 N ur 0% PSA 57.8 A˚ Metabolism: hydrolysis of ester, oxidation of thiophene to S log P 4.23 2-thiophenone, then hydrolysis of thioester

1/ ∗ . ∗ t 2 2–15 h V 0.7–1 1 PRASUGREL F 70–80%∗ CL 29–43∗ ∗deacetylated metabolite on oral O ∗ F pb 98% Mwt 373.4 dosing of prasugrel O 2 ur 0% PSA 74.8 A˚ Platelet inhibitor N O log P 3.17 Further metabolism: thiolactone S hydrolysis, then S-methylation and conjugation with cystein

1/ t 2 180 h V – ROLAPITANT F C F –CL–NK antagonist 3 O 1 O pb – Mwt 500.5 N 2 H ur – PSA 50.4 A˚ N log P 4.01 F3C H

1/ t 2 9–13 h V 1 APREPITANT F C F 60–65% CL 0.9–1.3 NK antagonist, antiemetic 3 O O 1 pb >95% Mwt 534.4 Metabolism: oxidation of 2 ur <5% PSA 75.2 A˚ morpholine N log P 4.23 F3C H F N O N N H

1/ ∗ H t 2 11 h V – GW597599 N F 71%∗ CL 15∗ ∗dog pb – Mwt 491.5 NK1 antagonist 2 N ur – PSA 35.6 A˚ CF log P 5.58 F O N 3

CF3

(continued overleaf ) 266 46 Arylalkylamines

t1/ 9–15 h V – CASOPITANT O 2 F 34% (dog) CL – NK1 antagonist, antiemetic, N pb High Mwt 616.6 anxiolytic, antidepressant 2 ur Negligible PSA 47.1 A˚ Metabolism: hydroxylation, N log P 5.59 N-deacetylation, N-dealkylations

N CF F O N 3

CF3

1/ t 2 25 h V – LY-517717 ∗ ∗ N F 25–82% CL – animals pb – Mwt 459.6 Factor Xa inhibitor, antithrombotic 2 ur – PSA 71.7 A˚ N log P 3.14

N H O N HN

47 Phenethylamines (2-Phenylethylamines)

The phenethylamine substructure can be found in numerous natural products and drugs. Depending on the precise substitution pattern, phenethylamines show different biological effects and have been used in various therapeutic areas, for example, as central nervous system (CNS) agents (stimulants, antidepressants, and appetite suppressants), cardiovascular agents, or antianginals (Tables 47.1 and 47.2).

47.1 Biological Activity of Phenethylamines

Phenethylamines with hydroxyl or bioequivalent groups, being structurally related to dopamine and adrenaline (epinephrine), are agonists or antagonists at dopamine, adrenaline, or serotonin receptors or have an effect on the metabolism or transport of these natural neurotransmitters (Scheme 47.1).

NH2 HO NH2

HO HO Tyramine Dopamine t1/2 0.5 h t1/2 2 min

OH OH OH H H HO NH2 HO N N

HO HO HO Noradrenaline Adrenaline Synephrine − − t1/2 2 3 min, F 3% t1/2 3 10 min t1/2 3 h, F 20%

Scheme 47.1 Natural phenethylamines.

Phenethylamines devoid of hydroxyl groups usually have little afﬁnity for adrenaline or dopamine receptors, but they may interact with monoamine oxidase (MAO) and the neuronal transport system for catecholamines. This interaction can enhance the levels of dopamine and noradrenaline in the CNS. Such nonphenolic phenethylamines, for example, amphetamine, are called

‘‘indirectly acting sympathomimetic drugs,’’ and their biological effects include CNS stimulation, attention enhancement, appetite suppression, and suppression of fatigue. Adrenaline agonists of low oral bioavailability have been developed for the treatment of glaucoma (as eye drops) or asthma (for inhalation).

47.2 Metabolism

Most natural small molecules present in the human body are metabolized rapidly by substrate-specific enzymes. Therefore, natural metabolites, such as natural amino acids, peptides, carbohydrates, steroids, or eicosanoids, tend to show poor pharmacokinetics and are not well suited as building blocks for drugs, unless short half-lives are the aim (as in prodrugs). This is also true for most natural phenethylamines. In particular, those with a catechol (o-dihydroxyphenol) substructure have short plasma half-lives, because enzymes quickly degrade these compounds. Catecholamines (2-(3,4- dihydroxyphenyl)ethylamines) are rapidly methylated at the phenolic 3-hydroxyl group by catechol-O-methyltransferase (COMT) or converted into O-sulfates by the sulfotransferases present in the gut wall (Scheme 47.2). Phenethylamines devoid of a benzylic hydroxyl group are oxidatively deaminated by MAO (α-hydroxylation of N-alkylamines followed by hydrolysis of the resulting hemiaminals). MAO can also be found in the epithelial mucosa of the intestine and can, therefore, contribute significantly to the first-pass metabolization, and strongly diminish oral bioavailability. Many N,N-dimethyl or N,N-diethyl phenethylamines are quickly N- dealkylated in vivo by MAO. Phenethylamines with an unsubstituted phenyl group may also be hydroxylated at the latter by liver enzymes (CYP 450 (cytochrome P450)).

COMT (O-methylation) sulfotransferases (O-sulfation) MAO (hydroxylation)

OH H HO NH2 N Compare to O O S HO N H Dopamine Sotalol t1/2 2 min, F low t1/2 12 h, F 95%

Scheme 47.2 Metabolism of dopamine.

Metabolization by COMT will not occur in phenethylamines devoid of a catechol substructure, and oxidation by MAO may be slowed by bulky N-alkyl groups (isopropyl, tert-butyl), by alkyl groups at the ethylene chain (e.g., α-methylation), or by heteroatoms or hydroxyl groups at the benzylic position or close to the nitrogen atom. Most phenethylamines devoid of phenolic OH groups can cross the blood–brain barrier. CNS penetration and absorption from the gastrointestinal (GI) tract may 47.3 Tetrahydroisochinolines and Related Compounds 269 be enhanced by increasing lipophilicity or by lowering the polar surface area (PSA). Oral bioavailability may also be enhanced by reducing the number of rotatable bonds. As for most basic drugs, the rate of renal excretion can be strongly enhanced if the urine is rendered acidic, for example, by administration of ammonium chloride to the patient. When metabolism by MAO and COMT has been blocked, renal excretion of the unchanged drug will often become half-life determining.

47.3 Tetrahydroisochinolines and Related Compounds

Opium, the dried juice of the unripe seed capsules of the poppy plant, Papaver somniferum, contains mainly two groups of alkaloids: the phenanthrene derivatives (10% morphine, 0.5% codeine, and 0.2% thebaine) and the 2-benzylisoquinoline derivatives (6% noscapine and 1% papaverine). However, other plants also produce alkaloids with an isoquinoline substructure, and more than 500 benzylisoquinoline alkaloids have been isolated to date. Many of these are biologically active and have been used in medicine directly or as leads for the development of synthetic analogs with improved selectivity or therapeutic index. Interestingly, although plants produce these compounds mainly as a defense against herbivores, isoquinoline alkaloids show a broad spectrum of pharmacological properties (Table 47.3). Isoquinolines and tetrahydroisoquinolines can be readily synthesized from phenethylamines with the Pictet–Spengler and Bischler–Napieralski reactions (Scheme 47.3).

OMe MeO OMe N MeO MeO MeO POCl3 OMe NH HN MeO 2 MeO Bischler− OMe O Napieralski

MeO Pd/C Papaverine ° N t 2 h, F 5−99% 250 C MeO 1/2 OMe Alkaloid contained in opium OMe

HO H O, pH 6 HO O 2 NH O 20 °C,18 h HO + NH O HO 2 O Pictet−Spengler O

Scheme 47.3 Synthesis of isoquinolines and tetrahydroisoquinolines. 270 47 Phenethylamines (2-Phenylethylamines)

Further Reading

(a) Sneader, W. (2001) The discovery and synthesis of epinephrine. Drug News Perspect., 14, 491–494; (b) Sneader, W. (2001) Epinephrine analogues. Drug News Perspect., 14, 539–543. Zhang, A., Zhang, Y., Branfman, A.R., Baldessarini, R.J., and Neumeyer, J.L. (2007) Advances in development of dopaminergic aporphinoids. J. Med. Chem., 50, 171–181.

Table 47.1 Phenethylamines and related compounds. V in l/kg; CL in ml min−1 kg−1; Mwt in g/mol.

1/ t 2 18 h V 3–6 AMPHETAMINE NH2 F 20–25% CL 9.7 CNS-stimulant, anorexic pb 15–40% Mwt 135.2 Metabolism: benzylic and ur 20–30% PSA 26.0 A˚ 2 aromatic 4-hydroxylation 1/ log P 1.5 N-Lys-amphetamine: t 2 0.5 h

1/ t 2 1–2 h V 2.7 TRANYLCYPROMINE F – CL 14 (racemic) pb – Mwt 133.2 Irreversible MAO inhibitor, NH2 ur – PSA 26.0 A˚ 2 antidepressant, CYP2A6 log P 1.4 inhibitor; Metabolism: N-acetylation, hydroxylation

1/ / . ± . t 2 1.6 h V F 1 58 0 32 BICIFADINE F >89% CL/F 15 ∗monkey; NMDA antagonist, pb 95–97%∗ Mwt 173.3 5-HT/norepinephrine ˚ 2 N ur 0% PSA 12.0 A reuptake inhibitor, analgesic H log P 2.15 Metabolism: oxidation to lactam (CHCH2NH to CHCONH), oxidation of CH3 to CO2H, then acyl glucuronidation

1/ t 2 6–21 h V 3–5 METHAMPHETAMINE H F 60–70% CL – CNS-stimulant, anorexic N pb – Mwt 149.2 Metabolism: N-demethylation, ur 30% PSA 12.0 A˚ 2 benzylic and aromatic log P 2.1 4-hydroxylation; withdrawn in 1973 for risk of abuse

t1/ 5h V – ETHYLAMPHETAMINE H 2 N F – CL – CNS-stimulant, anorexic pb – Mwt 163.3 Metabolism: aromatic ur 45% PSA 12.0 A˚ 2 4-hydroxylation log P 2.71

1/ t 2 2h V – DIETHYLPROPION, F – CL – DIETHYLCATHINONE, O pb – Mwt 205.3 AMFEPRAMONE N ur <5% PSA 20.3 A˚ 2 Anorexic; Metabolism: log P 2.6 N-deethylation, reduction of ketone, oxidative degradation, and conjugation to hippuric acid 271

1/ t 2 14–30 h V 8–10 FENFLURAMINE H F 60–70% CL 11 Anorexic; Metabolism: F3C N pb 30% Mwt 231.3 N-deethylation, N-oxidation ur 13±6% PSA 3.4 A˚ 2 and nitrone-formation; log P 3.5 withdrawn in 1997 because of risk of heart valve damage

1/ t 2 2h V – FENPROPOREX H F – CL – CNS-stimulant, anorexic N CN pb – Mwt 188.3 Metabolism: ur 5–9% PSA 35.8 A˚ 2 N-decyanoethylation, aromatic log P 2.04 4-hydroxylation

1/ ± t 2 2 1h V 1.9 SELEGILINE, DEPRENYL F 4.4% CL/F 1500 Irreversible MAO inhibitor, N pb 94% Mwt 187.3 antidepressant; Metabolism: ur Negligible PSA 3.2 A˚ 2 N-demethylation, log P 2.7 depropargylation, benzylic and aromatic 4-hydroxylation

1/ . ± . t 2 1 3 0 7h V 3.7 RASAGILINE H F 36% CL 24 MAO inhibitor, N pb 60–70% Mwt 171.2 antiparkinsonian ur <1% PSA 12.0 A˚ 2 Metabolism: log P 2.27 N-depropargylation

1/ > t 2 19–36 h V 30 TERBINAFINE F 40% CL – Antifungal; Metabolism: pb >99% Mwt 291.4 N-demethylation, hydroxylation ˚ 2 N ur Negligible PSA 3.24 A of tert-butyl, oxidation of log P 5.58 tert-butyl to carboxyisopropyl, N-de(naphthyl)methylation (to naphthaldehyde and naphthoic acid)

1/ ± t 2 24 8h V 3–4 PHENTERMINE NH2 F – CL – Anorexic; Metabolism (rat): pb 96% Mwt 149.2 N-hydroxylation, aromatic ur 70–80% PSA 26 A˚ 2 4-hydroxylation log P 2.3

1/ t 2 17–18 h V – MEPHENTERMINE H N F – CL – Anorexic; Metabolism: pb – Mwt 163.3 N-demethylation ur – PSA 12 A˚ 2 log P 2.6

(continued overleaf ) 272 47 Phenethylamines (2-Phenylethylamines)

1/ t 2 41 h V – CHLORPHENTERMINE NH2 F – CL – Anorexic; Metabolism: pb – Mwt 183.7 N-oxidation to N-hydroxy, Cl ur 17% PSA 26 A˚ 2 nitroso, nitro log P 2.8

1/ ± / t 2 11 2h V F 2.7 LORCASERIN > NH F 90% CL – 5-HT2C agonist for treatment Cl pb 70% Mwt 195.7 of obesity; Metabolites: < 2 1/ ± ur 1% PSA 12.0 A˚ N-sulfate (t 2 41 10 h), log P 2.89 N-carbamoyl glucuronide

1/ Cl t 2 10 min V 0.23–0.66 FENOLDOPAM HO F 5–7% CL 25–38 Dopamine agonist, NH pb 88% Mwt 305.8 antihypertensive < ˚ 2 HO ur 1% PSA 72.7 A Metabolism: O-sulfation, log P 2.06 O-methylation

1/ t 2 10–58 h V 6.4 VARENICLINE N F High CL – Nicotinic agonist for NH pb <20% Mwt 211.3 treatment of nicotine addiction ˚ 2 N ur 92% PSA 37.8 A Metabolism: glucuronidation, log P 0.74 N-formylation

1/ t 2 3–7 h V 0.84 BACLOFEN CO2H F 95% CL 2.6 Muscle relaxant, GABA

NH2 pb 30% Mwt 213.7 agonist; Metabolism: ur 70–80% PSA 63.3 A˚ 2 deamination to Cl log P 0.78 4-hydroxy-3-arylbutyric acid

1/ . ∗ t 2 8–20 h V 10 6 SIBUTRAMINE F –CL35∗∗rat pb 97% Mwt 279.8 Anorexic; Metabolism: N ur 0% PSA 3.2 A˚ 2 N-demethylation; 1/ log P 5.1 monodesmethyl: t 2 14 h; 1/ Cl didesmethyl: t 2 16 h; withdrawn 2010 for cardiovascular risk

1/ t 2 12–30 h V 20–25 FLUVOXAMINE MeO F 50–60% CL 15.2 5-HT reuptake inhibitor, O pb 77% Mwt 318.3 antidepressant; Metabolism: N NH 2 2 ur 3% PSA 56.8 A˚ oxidation of CH2OMe to log P 3.71 CO2H, N-acetylation, F3C replacement of NH2 by OH 273

1/ ± t 2 24 8h V – BENZPHETAMINE F – CL – Anorexic; Metabolism: N pb 75–99% Mwt 239.4 aromatic 4-hydroxylation, ur – PSA 3.2 A˚ 2 N-dealkylation log P 3.9

1/ t 2 14 h V – PRENYLAMINE H F 15% CL – Coronary vasodilator N Ph pb 97% Mwt 329.5 Metabolism: aromatic < . ˚ 2 Ph ur 0 1% PSA 12 A 4-hydroxylation, N-dealkylation log P 5.7

1/ t 2 – V – AMOROLFINE ∗ ∗ N F 70% CL – rat, dog O pb High Mwt 317.5 Topical antifungal ur – PSA 12.5 A˚ 2 log P 5.73

1/ F t 2 8–14 h V 3 SITAGLIPTIN CF3 NH2 F 87% CL – DPPIV inhibitor, antidiabetic N pb 38% Mwt 407.3 N N ur 79% PSA 77.0 A˚ 2 F N log P 1.30 F O

1/ t 2 5–12 h V 4.2–8.4 AMIFLAMINE NH2 F – CL 7–14 Antidepressant, MAO-inhibitor pb – Mwt 192.3 Metabolism: N-demethylation N ur 0.2% PSA 29.3 A˚ 2 log P 1.93

1/ t 2 1–2 h V 0.7–3.2 RIVASTIGMINE O F 35–72% CL 5.2–20 Nootropic, crosses bbb N pb 40% Mwt 250.3 Metabolism: hydrolysis of N O ur 0% PSA 32.8 A˚ 2 carbamate, N-demethylation log P 2.14

1/ t 2 3.5–4.0 h V – GEPEFRINE . ± . HO NH2 F 90–100% CL 1 8 0 3 Sympathomimetic, pb – Mwt 151.2 antihypotensive ur – PSA 46.3 A˚ 2 log P 1.11

1/ t 2 4.8 h V – PHOLEDRINE H α N F 20% CL – -Adrenergic agonist, pb – Mwt 165.2 antihypotensive, metabolite ur 3% PSA 32.3 A˚ 2 of methamphetamine HO log P 1.8 (continued overleaf ) 274 47 Phenethylamines (2-Phenylethylamines)

1/ . ± . / . ± . H t 2 4 6 1 0h V F 7 1 1 4 PENTAZOCINE F 47±15% CL/F 17±5 Analgesic; Metabolism: allylic N pb 65% Mwt 285.4 oxidation of CH3 to CH2OH ur 15±7% PSA 23.5 A˚ 2 and CO H HO 2 log P 4.15

1/ . ± . H t 2 2 5 0 3h V 11–12 DEZOCINE F – CL 50 Analgesic; Metabolism: pb – Mwt 245.4 O-glucuronidation, N-oxidation 2 HO NH2 ur <1% PSA 46.3 A˚ log P 3.68

1/ . ± . t 2 2–4 h V 8 3 1 5 TAPENTADOL F 32±7% CL 24±3 Opiate agonist, analgesic HO N pb 20% Mwt 221.3 Metabolism: glucuronidation, ur 3% PSA 23.5 A˚ 2 sulfation, N-demethylation log P 3.02

1/ ± t 2 2 1h V 5 MEPTAZINOL F 9% CL 30 Opioid analgesic pb 27% Mwt 233.4 g/mol Metabolism: HO N ur 0% PSA 23.5 A˚ 2 glucuronidation, log P 3.40 oxidation to lactam

1/ ∗ t 2 2.0–2.5 h V – PRECLAMOL F 4% CL – ∗im HO N pb – Mwt 219.3 Dopamine D2 agonist, ur – PSA 23.5 A˚ 2 antipsychotic; Metabolism: log P 2.74 O-sulfation

1/ t 2 12–14 h V 7.0–7.3 PRAMIPEXOLE H F 90% CL 0.11 Antiparkinsonian S N H N pb – Mwt 211.3 2 ˚ 2 N ur 90% PSA 79.2 A log P 1.42

1/ t 2 5–7 h V 2.3 ROTIGOTINE ∗ ∗ N F 0.5% CL – 37% transdermal pb 92% Mwt 211.3 Dopamine agonist, S ur – PSA 53.7 A˚ 2 antiparkinsonian; high log P 0.6 ﬁrst-pass effect; Metabolism: OH N-dealkylation, glucuronidation

1/ t 2 12–17 h V 1.5 QUINAGOLIDE H F 100% CL – Dopamine D agonist for N 2 O O pb 90% Mwt 395.6 treatment of elevated levels S ur – PSA 81.3 A˚ 2 of prolactin; Metabolites: N N H H log P 4.12 glucuronides, sulfates, OH N-desethyl, N-bis-desethyl 275

1/ H t 2 3h V – NOLOMIROLE N F – CL – Dopamine D2 and α2 pb – Mwt 333.4 adrenergic agonist for O O ur – PSA 64.6 A˚ 2 treatment of congestive O O log P 1.97 heart failure

1/ t 2 6–9 h V 6–7 3,4-METHYLENEDIOXY- H F – CL – METHAMPHETAMINE, O N pb 20% Mwt 193.2 MDMA, ECSTASY 2 O ur 20% PSA 30.5 A˚ Recreational drug log P 2.1 Metabolism: hydrolysis of acetal

1/ t 2 6h V – MESCALINE MeO NH2 F –CL–5-HT2A agonist, natural pb – Mwt 211.3 hallucinogenic; Metabolism: MeO ur 58% PSA 53.7 A˚ 2 oxidation to arylacetic and OMe log P 0.6 benzoic acids, O-demethylation, N-acetylation

1/ t 2 2–10 h V 7.5 ROPINIROLE O F 55% CL 6–12 Dopamine agonist, pb 10–39% Mwt 260.4 antiparkinsonian, crosses HN N ur <5% PSA 32.3 A˚ 2 bbb; Metabolism: log P 2.49 N-depropylation, aromatic 7-hydroxylation

1/ OMe t 2 1–2 h V 0.54 AGOMELATINE F <5% CL 17 Antidepressant; Metabolism: H pb 95% Mwt 243.3 O-demethylation, aromatic N ur 0.01% (iv) PSA 38.3 A˚ 2 3-hydroxylation (meta O log P 2.27 to amidoethyl)

1/ t 2 8h V 0.5 ROLIPRAM O F 74% CL 6.1 Antidepressant; only the pb – Mwt 275.3 R(−) isomer is active NH ˚ 2 O ur – PSA 47.6 A Metabolism: O-dealkylation, log P 2.00 cyclopentyl 2- and MeO 3-hydroxylation, pyrrolidone 5-hydroxylation

1/ O t 2 0.8–2.6 h V 2 RAMELTEON, TAK-375 F 0.5–12% CL 13 Melatonin MT1/MT2 agonist pb 82% Mwt 259.3 Metabolism: hydroxylation H < . ˚ 2 N ur 0 1% PSA 38.3 A of ethyl group, benzylic log P 2.29 hydroxylation O

(continued overleaf ) 276 47 Phenethylamines (2-Phenylethylamines)

1/ . ± . / ± t 2 4 9 2 4h V F 8 4 VENLAFAXINE F 10–60% CL/F 22±10 Antidepressant, ± HO pb 27 2% Mwt 277.4 serotonin-norepinephrine N ur 4.6±3% PSA 32.7 A˚ 2 reuptake inhibitor, racemate log P 3.3 Metabolism: N- and MeO O-demethylation

1/ ± t 2 10 4h V – O-DESMETHYL- F –CL– VENLAFAXINE HO pb 30±12% Mwt 263.4 Main active metabolite of N ur 29±7% PSA 43.7 A˚ 2 venlafaxine log P 3.3 HO

1/ t 2 5h V 1.5 CIRAMADOL F 82% CL 4.9 Analgesic; Metabolite: phenolic HO pb – Mwt 249.4 H glucuronide HO ur 40–50% PSA 43.7 A˚ 2 N log P 2.00

1/ t 2 7min V – DOPEXAMINE H F –CL36 HO N Cardiotonic NH pb – Mwt 356.5 2 HO ur – PSA 64.5 A˚ log P 3.23

1/ OH t 2 2–3 min V 0.2 DOBUTAMINE H F –CL60 Cardiotonic, usually given as HO N pb – Mwt 301.4 continuous infusion (iv) ur – PSA 72.7 A˚ 2 Metabolism: glucuronidation, HO log P 3.1 O-methylation of catechol

1/ t 2 1.5–2.0 h V 1.5 BEVANTOLOL Antianginal, antihypertensive, OH F 60% CL 4.4–6.9 H > antiarrhythmic MeO N O pb 95% Mwt 345.4 ur <1% PSA 60.0 A˚ 2 Metabolism: aromatic MeO log P 3.00 4-hydroxylation, oxidation of CCH3 to CCH2OH and CCO2H, then glucuronidation

1/ OMe t 2 1–3 h V – FALIPAMIL F –CL17±2 OMe Calcium channel blocker pb 88% Mwt 428.5 Metabolism: N-demethylation MeO N N ur 14% (iv) PSA 60.5 A˚ 2 O log P 1.48 MeO 277

1/ OMe t 2 2–3 h V – ZATEBRADINE F 50% CL – Antianginal OMe pb – Mwt 456.6 Metabolism: N- and MeO N N ur 12% PSA 60.5 A˚ 2 O-demethylation O MeO log P 4.48

1/ OMe t 2 2–11 h V 1.4 IVABRADINE F 40±10% CL 6.2 Antianginal MeO OMe N N pb 70% Mwt 468.6 Metabolism: N-demethylation MeO ur 4% PSA 60.5 A˚ 2 O log P 3.69

1/ . ± . . ± . t 2 4 0 1 5h V 5 0 2 1 VERAPAMIL F 22±8% CL 15±6 Antihypertensive, CN pb 90±2% Mwt 454.6 antianginal, MeO N OMe ur <3% PSA 64.0 A˚ 2 antiarrhythmic, CYP3A4 MeO OMe log P 4.5 substrate; active metabolite: N-desmethyl 1/ ± (t 2 9 3h)

1/ t 2 2.5–8.0 h V 2.1 GALLOPAMIL CN F 15–23% CL 6–17 Antianginal; Metabolism: MeO N OMe pb 93% Mwt 484.6 O-demethylation, MeO OMe ur <2% PSA 73.2 A˚ 2 N-dealkylation OMe log P 3.83

1/ t 2 13 h V – NEXOPAMIL CN F 23% CL 26–67 (dog) Calcium channel blocker, 5-HT2 N OMe pb 95–97% Mwt 404.6 antagonist, antihypertensive ur – PSA 54.7 A˚ 2 OMe log P 4.45 OMe

1/ ± t 2 5 3h V – FANTOFARONE MeO N F –CL– Calcium channel blocker; O MeO N pb – Mwt 550.7 antihypertensive ur – PSA 77.9 A˚ 2 Metabolite: N-desmethyl S 1/ ± O O log P 5.06 (t 2 4 1h)

(continued overleaf ) 278 47 Phenethylamines (2-Phenylethylamines)

1/ / O t 2 9–16 h V F 3.6–14.2 FIDUXOSIN F –CL/F 4.4–10.9 α O 1-Adrenoceptor antagonist for pb – Mwt 555.7 treatment of benign prostatic S N ur <1% PSA 125 A˚ 2 hyperplasia; orally available OMe N N log P 4.39 O N H N

1/ ∗ . ∗ t 2 0.8 h V 0 4 CARBOCROMEN F 25–30% CL – ∗ N acid pb – Mwt 361.4 Vasodilator ∗ EtO ur 20% PSA 65.1 A˚ 2 Metabolite: carboxylic acid O O O log P 3.70 O

t1/ 3–4 h V – MOROCROMEN O 2 F 67–79% CL – Cardiovascular agent N O pb – Mwt 401.5 ur 54–64% PSA 80.3 A˚ 2 N N O O log P 0.42 H O

1/ Ph Ph t 2 6–20 h V – ASIMADOLINE F 40–50% CL – Analgesic; Metabolism: O N pb 95–97% Mwt 414.5 glucuronidation, aromatic OH ˚ 2 N ur – PSA 43.8 A hydroxylation, oxidative ring log P 3.71 ﬁssion of pyrrolidine

1/ t 2 13–19 h V 2.6 DARIFENACIN F 15–19% CL 12 Muscarinic acetylcholine M3 Ph pb 98% Mwt 426.6 antagonist for treatment of Ph N ur 3% PSA 55.6 A˚ 2 urinary incontinence NH 2 log P 4.50 Metabolism: hydroxylation and O O ring-opening of dihydrobenzofuran, N-dealkylation of pyrrolidine

1/ t 2 – V – ZAMIFENACIN Ph F –CL0.65Muscarinic acetylcholine M3 N O O Ph pb 99.99% Mwt 415.5 antagonist for treatment of ur – PSA 30.9 A˚ 2 irritable bowel syndrom O log P 6.34 279

1/ H t 2 7–8 h V 3.2–3.6 DOFETILIDE N S F 92–96% CL 5.0–6.7 Antiarrhythmic N O O pb 60–70% Mwt 441.6 Metabolism: N-dealkylation, O O O ur 70% PSA 105 A˚ 2 S N-oxidation N log P 2.0 H

1/ ± t 2 9 4h V 0.23 TAMSULOSIN F 100% CL 0.5–0.7 For treatment of benign prostatic hypertrophy; CYP3A4 O pb 99% Mwt 408.5 O O H ur 11±3% PSA 99.9 A˚ 2 and 2D6 substrate S N Metabolism: aromatic H N O log P 2.6 2 hydroxylation (para to OR), MeO O-demethylation, O-deethylation, N-dealkylation (to 2-ethyloxyphenoxyacetic acid)

t1/ 13±8h V 0.8 SILODOSIN F C O 2 3 F 32% CL 2.6 α O H 1-Adrenoceptor antagonist N pb 97% Mwt 495.5 Metabolism: glucuronidation, H N O 2 ur <4% PSA 97.1 A˚ 2 oxidation of alcohol N log P 2.33

1/ t 2 17–25 h V 2–3 MIBEFRADIL F 70–90% CL 4–7 Calcium channel blocker, OMe pb >99% Mwt 495.6 antihypertensive ur <3% PSA 67.5 A˚ 2 Metabolism: ester hydrolysis, N O O log P 6.21 benzylic hydroxylation to N N secondary alcohol, then H oxidation to ketone, F N-dealkylation; withdrawn in 1998 because of drug–drug interactions

t1/ 7h V/F 133±69 ELIGLUSTAT OH 2 F High CL – Inhibitor of glucosylceramide O N pb – Mwt 404.5 synthase for treatment of HN ur <1.5% PSA 71.0 A˚ 2 Gaucher and Fabry disease O log P 3.61 O

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; bbb, blood–brain barrier; DPPIV, dipeptidylpeptidase IV; GABA, γ-aminobutyric acid; HT, hydroxytryptamine; NMDA, N-methyl D-aspartic. 280 47 Phenethylamines (2-Phenylethylamines)

Table 47.2 2-Aryl-2-hydroxyethylamines and related compounds. V in l/kg; CL in ml min−1 kg−1; Mwt in g/mol.

1/ / t 2 3–6 h V F 2.2–4.5 EPHEDRINE OH H F 85% CL/F 4.3–9.8 Bronchodilator N pb 0% Mwt 165.2 Metabolism: N-dealkylation, ur 22–99% PSA 32.3 A˚ 2 aromatic 4-hydroxylation, then log P 1.2 conjugation

1/ . ± . / . ± . OH t 2 4 7 0 4h V F 4 1 0 9 PHENYLPROPANOLAMINE F >70% CL/F 10±3 Decongestant, anorexic, NH 2 pb – Mwt 151.2 bronchodilator; withdrawn in ur 65±10% PSA 46.3 A˚ 2 2000 because of stroke risk log P 0.3

t1/ 10–19 h V – METHYLAMINOREX NH2 2 F 62% CL – Stimulant, anorexic, and O N pb – Mwt 176.2 recreational drug (racemic cis ur – PSA 47.6 A˚ 2 isomer) log P 1.32

1/ t 2 16–31 h V – PHENMETRAZINE O F –CL– Anorexic NH pb – Mwt 177.3 Metabolism: N- and ur 19% PSA 21.3 A˚ 2 O-dealkylation log P 1.86

t1/ 19–24 h V – PHENDIMETRAZINE O 2 F –CL– Anorexic N pb – Mwt 191.3 Metabolism: N-demethylation, ur – PSA 12.5 A˚ 2 N-oxidation log P 2.1

t1/ 3.3±1.0h V 0.73±0.28 VILOXAZINE O 2 F 85±14% CL 124±11 Antidepressant O NH pb – Mwt 237.3 Metabolism: aromatic 4- and ur – PSA 39.7 A˚ 2 5-hydroxylation O log P 1.3

1/ t 2 2.2 h (rat) V – INDELOXAZINE O F –CL– Antidepressant, nootropic O NH pb – Mwt 231.3 Metabolism (rat): ur – PSA 30.5 A˚ 2 dihydroxylation of alkene, log P 1.79 N-acetylation, oxidative degradation of morpholine ring 281

t1/ 4±2h V – TULOBUTEROL Cl OH 2 H F 40% CL – Bronchodilator N pb – Mwt 227.7 Metabolism: aromatic ur 14% PSA 32.3 A˚ 2 hydroxylation (para to alkyl) log P 2.7

1/ ± / . ± . t 2 12 4h V F 7 2 1 6BUPROPION ∗ ± ∗animals; antidepressant, O F 5–20% CL/F 35 9 H ± dopamine–norepinephrine Cl N pb 84 2% Mwt 239.8 ur <1% PSA 29.1 A˚ 2 reuptake inhibitor log P 3.4 Metabolism: reduction of ketone to alcohol, hydroxylation of tert-butyl, then hemiacetal formation

1/ . ± . t 2 2.3 h V 1 8 0 7 KETAMINE O F 20±7% CL 15±5 Anesthetic (iv); NMDA NH pb 12–47% Mwt 237.7 (N-methyl aspartate) antagonist ur 4% PSA 29.1 A˚ 2 Metabolism: N-demethylation, log P 2.27 dehydrogenation to conjugated Cl cyclohexenone

1/ ∗ t 2 5h V – SOLABEGRON OH ∗ ∗ H F 46% CL – monkey Cl N β N pb – Mwt 227.7 3 adrenergic agonist, H ur 14% PSA 32.3 A˚ 2 treatment of overactive bladder log P 2.7 and irritable bowel syndrom CO H 2 Metabolism: acyl glucuronidation

1/ t 2 23–32 h V – CLOBUTINOL N F –CL– Antitussive pb Low Mwt 255.8 Metabolite: N-desmethyl; OH ur – PSA 23.5 A˚ 2 withdrawn 2007 for causing Cl log P 3.26 cardiac arrhythmias

1/ t 2 3–7 h V – NORFENEFRINE OH F 20% CL – Adrenergic

HO NH2 pb – Mwt 410.9 Metabolism: glucuronidation, ur – PSA 81.6 A˚ 2 sulfation, oxidative deamination log P 4.4 to hydroxymandelic acid and (hydroxyphenyl)ethyleneglycol

(continued overleaf ) 282 47 Phenethylamines (2-Phenylethylamines)

1/ ∗ t 2 0.3–1.0 h V – METARAMINOL OH F –CL– ∗iv HO NH2 pb 45% Mwt 167.2 Adrenergic ur – PSA 66.5 A˚ 2 log P −0.2

1/ t 2 2.1–3.4 h V 2.6–5.0 PHENYLEPHRINE OH H F 38% CL – Mydriatic, decongestant HO N pb – Mwt 167.2 Metabolism: O-glucuronidation, ur 2.6% PSA 52.5 A˚ 2 O-sulfation, oxidation (by MAO) log P 0.4 to 3-hydroxymandelic acid, deamination to diol

t1/ 2±1h V 2.1 ETILEFRIN OH 2 H F 35% CL 14 Antihypotensive HO N pb 23% Mwt 181.2 Metabolism: O-sulfation ur – PSA 52.5 A˚ 2 log P 0.4

t1/ 2.5 h V – OCTOPAMINE OH 2 F 25% CL – Adrenergic NH 2 pb – Mwt 153.2 Metabolism: deamination, ur – PSA 66.5 A˚ 2 conjugation HO log P −0.6

1/ t 2 2–3 h V – OXEDRINE, SYNEPHRINE OH H F 10–20% CL – Adrenergic, vasopressor N pb – Mwt 167.2 Metabolism: O-sulfation, ur 2.5% PSA 52.5 A˚ 2 O-glucuronidation, HO log P 0.4 deamination to hydroxymandelic acid and 2-(hydroxyphenyl)glycol

1/ t 2 2.5 h V 2.5–5.0 BAMETHAN OH H F 75% CL – Vasodilator N pb – Mwt 209.3 ur 30% PSA 52.5 A˚ 2 HO log P 1.9

1/ t 2 1.7–2.6 h V 7 RITODRINE OH H N F 30% CL 23 Tocolytic pb 25–35% Mwt 287.4 Metabolism: glucuronidation, 2 HO OH ur 35% PSA 72.7 A˚ sulfation log P 2.1 283

1/ O t 2 10 h V – FORMOTEROL OH H F –CL– Antiasthmatic HN N pb 61–64% Mwt 344.4 Metabolism: O-demethylation, ur 10% PSA 90.8 A˚ 2 glucuronidation, sulfation, HO OMe log P 2.2 N-deformylation

t1/ 1.3 h V – ISOXSUPRINE OH 2 H F 2.2% CL – β-Adrenergic agonist, N OPh pb – Mwt 301.4 vasodilator ur – PSA 61.7 A˚ 2 HO log P 2.8

t1/ 1h V – IFENPRODIL OH 2 F 5% CL – Vasodilator N pb – Mwt 325.5 ur – PSA 43.7 A˚ 2 HO log P 3.6

t1/ 16–20 h V – ELIPRODIL OH 2 F 47% CL – NMDA antagonist N F pb – Mwt 347.9 Metabolism: glucuronidation ur – PSA 23.5 A˚ 2 Cl log P 4.71

t1/ 2–20 h V 4.4–6.5 TRAXOPRODIL OH 2 Glutamate (NMDA) antagonist, OH F 23–62% CL 4–27 pb 37% Mwt 327.4 neuroprotectant N ur 6% PSA 63.9 A˚ 2 Metabolism: hydroxylation to log P 1.75 catechol, then O-methylation, HO glucuronidation, sulfation

1/ O t 2 4h V 1.4 PROCATEROL OH H F 40% CL – Bronchodilator HN N pb – Mwt 290.4 Metabolism: glucuronidation ur 20% PSA 85.3 A˚ 2 HO log P 1.7

1/ t 2 116–182 h V 39 INDACATEROL O ∗ ∗ OH H F 43% CL 6 inhaled, 33% (dog, po) HN N pb 95% Mwt 392.5 Adrenergic agonist, ur <2% PSA 81.6 A˚ 2 bronchodilator HO log P 3.88 Metabolism: hydroxylation, phenol-glucuronidation, N-dealkylation (continued overleaf ) 284 47 Phenethylamines (2-Phenylethylamines)

t1/ 3h V 1.9–2.7 FENOTEROL OH H 2 HO N F 2–5% CL – Bronchodilator, tocolytic pb 50–55% Mwt 303.4 Metabolism: O-sulfation, OH ur 60% PSA 92.9 A˚ 2 O-glucuronidation OH log P 1.5

1/ ± . ± . OH t 2 14 2h V 1 8 0 2 TERBUTALINE H F 14±2% CL 3.4±0.6 HO N Bronchodilator, tocolytic pb 20% Mwt 225.3 Metabolism: O-sulfation ur 56±4% PSA 72.7 A˚ 2 log P 1.4 OH

1/ OH t 2 9–15 h V 1.6 BAMBUTEROL H F 12–20% CL – N O N Bronchodilator pb 45% Mwt 367.4 Metabolism: hydrolysis of O ur – PSA 71.6 A˚ 2 carbamates log P 1.4 N O

1/ OH t 2 2–6 h V 7.6 ORCIPRENALINE, H HO N F 10–40% CL 14 METAPROTERENOL pb 10% Mwt 211.3 Bronchodilator ur – PSA 72.7 A˚ 2 Metabolism: O-sulfation log P 1.0 OH

t1/ 3min V – ISOPROTERENOL OH 2 H F 25% CL – Bronchodilator HO N pb – Mwt 211.3 Metabolism: aromatic ur 40% PSA 72.7 A˚ 2 O-methylation by COMT HO log P 0.32

1/ OH t 2 3min(iv) V – RIMITEROL H HO N F –CL– Bronchodilator pb – Mwt 223.3 Metabolism: O-sulfation, H ur 2% PSA 72.7 A˚ 2 O-methylation HO log P 0.74

t1/ 2.7–5.0 h V 1.6–2.5 SALBUTAMOL, ALBUTEROL OH 2 H F 43–50% CL 6.8–7.7 Bronchodilator, tocolytic N HO pb 8% Mwt 239.3 Metabolism: phenol sulfation ur 51–64% PSA 72.7 A˚ 2 HO log P 1.4 285

1/ OH t 2 2–3 h V – PIRBUTEROL H N N F 60% CL – Bronchodilator HO pb – Mwt 240.3 Metabolism: sulfation ˚ 2 HO ur 10% PSA 85.6 A log P 0.4

t1/ 9±3h V – SALMETEROL OH 2 H F –CL– Racemate, bronchodilator, N HO pb 96% Mwt 415.6 CYP3A4 substrate Ph ur <5% PSA 82 A˚ 2 Metabolism: benzylic HO O log P 4.2 hydroxylation

1/ . ± . . ± . t 2 4 9 2 0h V 9 4 3 4 LABETALOL O OH H F 18±5% CL 25±10 Antihypertensive, four N pb 50% Mwt 328.4 stereoisomers H2N ur <5% PSA 95.6 A˚ 2 Metabolism: phenol HO log P 2.7 glucuronidation, N-dealkylation to 3-amino-1-phenylbutane

1/ t 2 11–16 h V 16 MEDROXALOL O O OH H F 30–64% CL 16 Vasodilator N O pb – Mwt 372.4 H2N ur 8% PSA 114 A˚ 2 HO log P 2.57

1/ t 2 3–5 h V 0.75 AMOSULALOL MeO OH F >93% CL 1.9 Antihypertensive O O H S N pb 97–98% Mwt 380.5 Metabolism: aromatic H2N O ur 35% PSA 119 A˚ 2 hydroxylation (para to alkoxy), log P 1.01 benzylic hydroxylation, O-demethylation

1/ OH t 2 6–9 h (iv) V 11–15 IBUTILIDE F 3% CL 24–31 Antiarrhythmic N O O pb 41% Mwt 384.6 Metabolism: hydroxylation and S ur <5% PSA 78.0 A˚ 2 oxidative degradation of heptyl N H log P 4.17 group

1/ t 2 3–4 h V 4–8 DESGLYMIDODRINE OH F 93%∗ CL 20–30 Antihypotensive, MeO NH2 pb Low Mwt 197.2 vasoconstrictor, does not cross ur 80% PSA 64.7 A˚ 2 bbb ∗ OMe log P −0.03 drug on oral administration of its prodrug midodrine Metabolism: O-demethylation (continued overleaf ) 286 47 Phenethylamines (2-Phenylethylamines)

1/ OH t 2 25 min V – MIDODRINE H F –CL– MeO N Prodrug of desglymidodrine NH2 pb low Mwt 254.3 O ur 2–3% PSA 93.8 A˚ 2 OMe log P −0.4

1/ t 2 3.6 h V 3.3 BUFURALOL OH H F 46±15% CL 10.7 Antianginal, antihypertensive O N pb – Mwt 261.4 Metabolism: aromatic and ur <1% PSA 45.4 A˚ 2 benzylic hydroxylation, then log P 3.5 oxidation of benzylic alcohol to ketone

1/ ± / . ± . OH t 2 12 3h V F 2 0 0 4 SOTALOL H . ± . N F 90–100% CL/F 2 6 0 5 Antianginal, antiarrhythmic, O O pb 0% Mwt 272.4 antihypertensive S ur >75% PSA 78.4 A˚ 2 N H log P 0.8

1/ ∗ . ∗ OH t 2 1h V 4 1 CIMATEROL H F –CL– ∗ NC N steer, im pb – Mwt 219.3 Repartitioning agent ur – PSA 82.1 A˚ 2 H N 2 log P 0.65

1/ OH t 2 34 h V – CLENBUTEROL H Cl N F 89–98% CL – Bronchodilator, tocolytic pb >90% Mwt 277.2 Metabolism: aromatic ur 67% PSA 58.3 A˚ 2 N-hydroxylation H2N log P 2.8 Cl

1/ OH t 2 20–30 h V 5.8 MABUTEROL H F >91% CL 3.0 Bronchodilator, antiasthmatic F3C N pb – Mwt 310.8 Metabolism: CH3 hydroxylation ur 24–64% PSA 58.3 A˚ 2 H N 2 log P 3.0 Cl 287

Table 47.3 Tetrahydrochinolines, tetrahydroisochinolines, and related compounds. V in l/kg; CL in ml min−1 kg−1; Mwt in g/mol.

t1/ 1.0–2.5 h V – OXAMNIQUINE HO 2 H F Good CL – Anthelmintic N pb – Mwt 279.3 Metabolism: oxidation of O2N N H ur – PSA 90.1 A˚ 2 alcohol to carboxyl group log P 2.02

t1/ 12 min V – SALSOLINOL HO 2 F –CL– Endogenous neurotoxin, NH pb – Mwt 179.2 contained in chocolate HO ur – PSA 52.5 A˚ 2 log P 0.85

1/ ± ∗ . ± . t 2 41 15 min V 1 6 0 5 APOMORPHINE ∗ F 2% CL 40±15 iv N pb 94% Mwt 267.3 Emetic, crosses bbb H < ˚ 2 HO ur 1% PSA 43.7 A Metabolism: N-demethylation, log P 1.70 O-sulfation, and O-glucuronidation HO

1/ EtO t 2 7–12 h V 3 DROTAVERINE F 25–91% CL 3.5 Phosphodiesterase IV inhibitor, NH pb 80–95% Mwt 397.5 antispasmodic EtO ur – PSA 49.0 A˚ 2 OEt log P 3.91

OEt

1/ MeO t 2 2h(iv) V 1 PAPAVERINE F 5–99% CL 11 Vasodilator, opium alkaloid N pb 93% Mwt 339.4 MeO Metabolism: demethylation ur <1% PSA 49.8 A˚ 2 OMe log P 2.93

OMe

t1/ 2–8 h V – TETRABENAZINE MeO 2 F 5–7% CL – Antidyskinetic, antipsychotic N pb 82–85% Mwt 317.4 Metabolism: reduction of MeO H ur 0% PSA 38.8 A˚ 2 ketone to alcohol, log P 2.93 O-demethylation O

(continued overleaf ) 288 47 Phenethylamines (2-Phenylethylamines)

1/ O t 2 1–2 h VV PRAZIQUANTEL F Low CL – Anthelmintic, crosses bbb N pb – Mwt 312.4 ur – PSA 40.6 A˚ 2 N log P 2.66

1/ ∗ MeO t 2 10–13 h V – CARMEGLIPTIN ∗ F 28–174%∗ CL – animals N MeO pb – Mwt 377.5 DPPIV inhibitor, antidiabetic; H ur 36%∗ PSA 68.0 A˚ 2 little metabolism N F log P 1.21 H N 2 O

t1/ 13–19 h V – ALMOREXANT MeO 2 HN F –CL– Orexin antagonist, hypnotic N pb – Mwt 512.6 MeO O ur – PSA 50.8 A˚ 2 log P 5.89 F3C

t1/ 2–4 h V 4.7 NOSCAPINE O 2 H F 30% CL 22 Antitussive, opium alkaloid O N pb – Mwt 413.4 Metabolism: O-demethylation, ur <1% PSA 75.7 A˚ 2 cleavage of C−C bond between MeO H O log P 2.39 lactone and piperidine

O OMe MeO

1/ ∗ HO t 2 17–100 h V 17–47 TRABECTEDIN, ET-743 F – CL 13–35 ∗iv NH OMe pb >95% Mwt 761.8 Antineoplastic MeO < ∗ ˚ 2 O HO ur 1% PSA 194 A AcO O S log P 1.87 N N O O OH 289

1/ . ± . . ± . MeO t 2 2 0 1 1h V 0 39 0 14 D-TUBOCURARINE F Low CL 1.9±0.6 Neuromuscular blocking agent N pb 50±8% Mwt 609.7 HO ur 63±35% PSA 80.6 A˚ 2 O log P 1.99

N O OH

OMe

1/ . ± . . ± . MeO t 2 4 7 0 9h V 0 35 0 04 METOCURINE F –CL1.3±0.3 Neuromuscular blocking agent N ± MeO pb 35 6% Mwt 652.8 ˚ 2 O ur 50% PSA 55.4 A log P −1.41

N O OMe

OMe

1/ t 2 1.2–1.6 h V 0.12–0.22 DOXACURIUM O MeO F – CL 1.5–2.7 Neuromuscular blocking agent N O pb 28–42% Mwt 1035.2 MeO ur 24–38% PSA 163.4 A˚ 2 OMe OMe log P −1.76

OMe OMe 2

1/ t 2 0.8 h (iv) V 0.2 MIVACURIUM MeO O F – CL 55–70 Mixture of stereoisomers N MeO O pb 30% Mwt 1089.3 2 OMe OMe ur 0% PSA 163.4 A˚ log P −0.23 OMe OMe 2

(continued overleaf ) 290 47 Phenethylamines (2-Phenylethylamines)

t1/ 0.3–0.4 h V 0.16±0.06 ATRACURIUM MeO 2 F –CL6.2±2.0 Neuromuscular blocking agent; N O pb 38% Mwt 929.2 mixture of stereoisomers MeO CH2 ur 6–11% PSA 126.5 A˚ 2 MeO O log P −1.59 MeO 2

1/ Br t 2 52–63 h V 3.8–4.2 BROMOTETRANDRINE MeO F –CL11 Induces reversal of P-gp pb 78% Mwt 701.7 mediated multidrug resistance MeO N ur 0.6% PSA 61.9 A˚ 2 OMe log P 4.28 O

OMe O N 291

48 Aminoalkylindoles and Indole Alkaloids

In the 1970s, it was proposed that migraine may be caused by a disturbance of the extracranial circulation. Selective serotonin agonists were then sought, which were able to induce vasoconstriction of the extracranial blood vessels [1]. One of the ﬁrst antimigraine drugs based on this mechanism of action was sumatriptan (1984), a selective 5-hydroxytryptamine (5-HT)1B/1D agonist. Sumatriptan and other ‘‘triptans’’ (Table 48.1) are more selective than the earlier used ergot alkaloid derivatives (e.g., ergotamine). These derivatives show more side effects than triptans, such as nausea, vomiting, and leg weakness. Another group of therapeutically relevant indole derivatives are the vinca alkaloids (e.g., vincristine). These are speciﬁc tubulin ligands, which block the mitosis of cells and induce apoptosis. Vinca alkaloids can be used to treat a variety of cancers. Indoles are electron-rich, chemically reactive heteroarenes. Position 3 is particularly nucleophilic, but this position is blocked in most indole-containing drugs. Stabilization toward oxidation or electrophiles may also be achieved with electron-withdrawing substituents. Bioisosteres of indoles include benzimidazoles or benzothiazoles, which are more stable and easier to prepare than substituted indoles.

Reference

1. (a) Nichols, D.E. and Nichols, C.D. (2008) Serotonin receptors. Chem. Rev. 108, 1614–1641; (b) Sneader, W. (1996) Ergot and its alkaloids, Drug News Perspect., 9, 253–256.

Table 48.1 Aminoalkylindoles, indole alkaloids, and related compounds. V inlkg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ t 2 0.5–1.0 h V 0.6 MELATONIN F 100%∗ CL – ∗monkey N pb 61–85% Mwt 232.3 Natural hormone; induces MeO H O ur – PSA 54.1 A˚ 2 pigment lightening in skin cells N log P 1.04 Metabolism: aromatic H 6-hydroxylation, then O-sulfation

1/ t 2 6h V – OXITRIPTAN, CO2H F 50–85% CL – 5-HYDROXYTRYPTOPHAN pb 60% Mwt 220.2 Prodrug of serotonin, HO NH2 ur – PSA 99.3 A˚ 2 antidepressant, antimigraine; log P −0.29 crosses bbb N Metabolism (in CNS): H decarboxylation, then oxidation to hydroxyindolylacetic acid

t1/ Short V – SEROTONIN NH 2 HO 2 F 0% CL – Natural hormone pb – Mwt 176.2 Metabolism: O-methylation and N ur – PSA 62.0 A˚ 2 N-acetylation to melatonin, H log P 0.55 oxidative deamination

1/ t 2 1.5–2.9 h V 1.3–2.2 RIZATRIPTAN F 35–47% CL 12–19 5-HT1B,1D agonist, antimigraine, N pb 14% Mwt 269.3 crosses bbb N N ur 8–35% PSA 49.7 A˚ 2 Metabolism: oxidation to log P 0.96 N-oxide and N N H triazolomethylindole-3-acetic acid, aromatic 6-hydroxylation, N-demethylation

1/ t 2 2.3–3.0 h V 7 ZOLMITRIPTAN H N N F 36–60% CL 8.7 5-HT1B,1D agonist, antimigraine O pb 14–25% Mwt 287.4 Metabolites: N-oxide, < 2 1/ O N ur 10% PSA 57.4 A˚ N-desmethyl (t 2 2–4 h), H log P 1.64 oxidation to indole-3-acetic acid

t1/ 1.9±0.3h V 0.65±0.10 SUMATRIPTAN H N 2 N F 14±5% CL 16±2 S Antimigraine O O pb 14–21% Mwt 295.4 Metabolism: oxidation to N ur 22±4% PSA 73.6 A˚ 2 indole-3-acetic acid (by MAO) H log P 0.44 293

1/ t 2 3–4 h V 2.6–2.8 ALMOTRIPTAN F 69–80% CL 8.9–9.5 Antimigraine N N pb 23–40% Mwt 335.5 Metabolism: oxidation to S ur 40–65% PSA 64.8 A˚ 2 indole-3-acetic acid (by MAO), O O N log P 1.89 N-demethylation, oxidative ring H opening of pyrrolidine to 4-aminobutyric acid

1/ t 2 3.6–7.0 h V 2–3 ELETRIPTAN O O F 50% CL 9 Antimigraine N S pb 85% Mwt 382.5 Metabolism: N-demethylation, ur 85% PSA 61.6 A˚ 2 oxidation to N-oxide N H log P 3.08

1/ t 2 5–7 h V 2.4 NARATRIPTAN N F 63–74% CL 6.6 5-HT1A,1B,1D,1F agonist, pb 20–31% Mwt 335.5 antimigraine O O ur 50% PSA 73.6 A˚ 2 Metabolite: N-oxide S log P 1.35 N H N H

1/ HN t 2 24–30 h V 3.6 FROVATRIPTAN O F 18–30% CL 2.5 5-HT1B,1D agonist, antimigraine pb 15% Mwt 243.3 Metabolism: N-demethylation, H2N ur 2–10% PSA 70.9 A˚ 2 then N-acetylation of aliphatic N log P 0.85 amine, aromatic hydroxylation H

1/ O t 2 2–3 h V – RAMATROBAN O ∗ ∗ ∗ HN S F 100% CL 12 dog pb >95% Mwt 416.5 PGD2,PGH2,andTxA2 ur <8% PSA 96.8 A˚ 2 antagonist log P 3.02 Metabolism: acyl F glucuronidation N CO2H

1/ t 2 1–7 h V – PIRLINDOLE F 20–30% CL – MAO inhibitor, antidepressant; pb – Mwt 226.3 active metabolite: N NH ur – PSA 17.0 A˚ 2 dehydropirlindole (nonchiral log P 3.62 imine) (continued overleaf ) 294 48 Aminoalkylindoles and Indole Alkaloids

1/ H t 2 2–11 h V –DELAVIRDINE N F >51% CL – Reverse transcriptase inhibitor, N pb 98% Mwt 456.6 antiviral N ur <5% PSA 119 A˚ 2 Metabolism: N-dealkylation, H log P −1.23 pyridine hydroxylation N S N O O N O H

1/ t 2 8–10 h V 0.9 AVITRIPTAN F 17% CL 6.4 Antimigraine N H N 1/ N pb – Mwt 458.6 Metabolites: N-desmethyl (t 2 S MeO 2 1/ ur – PSA 112 A˚ 11 h), O-desmethyl (t 2 5h) O O N log P 1.58 Further metabolism: N-dealkylation

1/ O t 2 11–31 h V 0.4 PANOBINOSTAT OH F 30% CL 7.3 Histone deacylase inhibitor H N − N H pb – Mwt 349.4 Metabolism: reductive N O ur – PSA 77.2 A˚ 2 bond cleavage, amide hydrolysis, log P 3.62 oxidative degradation of N cinnamic acid, glucuronidation H

1/ SMe t 2 15–42 h V 17–32 PERGOLIDE F 20% CL 22–28 Antiparkinsonian pb 90% Mwt 314.5 Metabolites: despropyl, H ˚ 2 N ur – PSA 44.3 A sulfoxide, and sulfone; H log P 3.90 withdrawn in 2007 because of hepatotoxicity HN

1/ O t 2 1.6 h V 1.3–1.7 TERGURIDE F 20–32% CL 17 Antiparkinsonian, HN N pb – Mwt 340.5 antihyperprolactinemic ur – PSA 51.4 A˚ 2 H N log P 2.20 H

HN 295

1/ O t 2 1.5–2.0 h V 2.3 LISURIDE F 20% CL 10–20 Antimigraine, prolactin HN N pb 15% Mwt 338.5 inhibitor, antiparkinsonian ur 0% PSA 51.4 A˚ 2 Metabolism: N-deethylation, N log P 3.21 aromatic hydroxylation, H oxidation of both alkenes

1/ t 2 3–5 h V 0.28 LSD 5-HT , agonist, synthetic O N F High CL – 2A 2C pb 90% Mwt 323.4 hallucinogenic ur Low PSA 39.3 A˚ 2 Metabolism: oxidation of indole log P 2.71 to 2-indolone, N-deethylation, N N-demethylation H

1/ ± H t 2 4 1h V 0.5–1.0 METHYLERGOMETRINE, O N F 85% CL 7.7 METHYLERGONOVINE pb 35% Mwt 339.4 Oxytocic, metabolite of OH ur 3% PSA 68.4 A˚ 2 methysergide N log P 2.99 H

1/ H t 2 1h V –METHYSERGIDE O N F 13% CL 72–104 (rat) Antimigraine pb 84% (rat) Mwt 353.5 Metabolism: N-demethylation OH ur – PSA 57.5 A˚ 2 of indole to methylergometrine N log P 1.81 H

1/ t 2 63–69 h V –CABERGOLINE N F 63% (rat) CL 47 Prolactin inhibitor, crosses bbb H O N N pb 40–42% Mwt 451.6 Metabolism: hydrolysis of ur 10% PSA 71.7 A˚ 2 acylurea, N-dealkylation of O log P 2.43 imide, and piperidine H N H

(continued overleaf ) 296 48 Aminoalkylindoles and Indole Alkaloids

1/ ± ± H t 2 7 5h V 2 1 BROMOCRIPTINE O N O OH F 3–6% CL 5±6 Dopamine agonist for treatment pb 93% Mwt 654.6 of hyperprolactinemia N H N ˚ 2 O ur 2% PSA 118 A Metabolism: hydroxylation of N log P 8.6 proline O H

HN Br

1/ ± H t 2 15–20 h V 22 4 DIHYDROERGOCRYPTINE O N O OH F 2–3% CL – Dopamine agonist for treatment pb 45–64% Mwt 577.7 of Parkinson disease; crosses N H N ur – PSA 118 A˚ 2 bbb H O N log P 6.37 O H

1/ H t 2 14 h V 16 DIHYDROERGOCRISTINE O N O OH F –CL285-HT antagonist, vasoconstrictor pb 68% Mwt 611.7 GI absorption: 25% N H N ur <1% PSA 118 A˚ 2 H O N log P 6.55 O H

1/ t 2 9–13 h V 15–30 DIHYDROERGOTAMINE H ∗ O N O OH F 1%∗ CL 14.3 nasal: 38% pb 93% Mwt 583.7 Vasoconstrictor; high ﬁrst-pass N H N ur – PSA 118 A˚ 2 effect H O N log P 5.69 Absorption from GI tract: 30% O H Metabolite: 8-hydroxy

1/ H t 2 2.1 h (iv) V 3.6 ERGOTAMINE O N O OH F 2% CL 15 Antimigraine pb 98% Mwt 581.7 N H N ur – PSA 118 A˚ 2 O N log P 7.37 O H

HN 297

1/ H t 2 3.5 h V 15 ERGOLOID, O N O OH F 9–25% CL 25 DIHYDROERGOTOXINE pb 98–99% Mwt 591.8 Nootropic for the treatment of N H N ur 11% PSA 118.2 A˚ 2 Alzheimer disease H O N log P 3.07 O H

1/ OH t 2 1.0–1.5 h V 24 VINBLASTINE F – CL 10.6 N Antineoplastic pb 75% Mwt 810.97 Metabolism: O-deacetylation N ˚ 2 H ur – PSA 154 A log P 5.92 MeO2C N MeO H H N OAc HO CO2Me

1/ OH t 2 1.0–2.5 h V 8.6 VINCRISTINE F –CL1.8 N Antineoplastic pb 75% Mwt 825.0 N ˚ 2 H ur 12% PSA 171 A log P 5.75 MeO2C N MeO H H N OAc O HO CO2Me

1/ t 2 20–40 h V 76 VINORELBINE F 12–59% CL 17–21 N Antineoplastic pb 98% Mwt 778.9 N ˚ 2 H ur 11% PSA 134 A log P 7.08 MeO2C N MeO H H N OAc HO CO2Me

(continued overleaf ) 298 48 Aminoalkylindoles and Indole Alkaloids

t1/ 35 h (iv) V 5VINDESINE OH 2 F –CL2.2Antineoplastic N pb – Mwt 753.9 N ur – PSA 165 A˚ 2 H H log P 4.94 MeO2C N MeO H H N OH HO CONH2

1/ F F t 2 40 h (iv) V 35 VINFLUNINE F 57% CL 10 Antineoplastic N pb 67% Mwt 816.9 Metabolite: O-desacetyl ˚ 2 1/ N ur – PSA 134 A (t 2 120 h) H log P 4.12 MeO2C N MeO H H N OAc HO CO2Me

1/ t 2 1.6 h V 6.2 AJMALINE HO F 20% CL 9.8 Antihypertensive, antiarrhythmic pb 29–61% Mwt 326.4 Metabolism: aromatic ur 4% PSA 46.9 A˚ 2 mono- and dihydroxylation, then H log P 1.81 O-methylation, reduction of N N OH H aminal to piperidine, oxidation of both hydroxyl groups to carbonyl groups, N-oxidation

1/ . ± . t 2 2 5 0 5h V 3.8 (rat) VINPOCETINE F 57% CL 13±2 Vasodilator, nootropic H N pb 66% Mwt 350.5 Metabolism: hydrolysis of ester N ur 0% PSA 34.5 A˚ 2 log P 3.98 EtO2C

1/ t 2 1–6 h V 2 (rat) VINCAMINE F 58% (rat) CL – Vasodilator, crosses bbb H pb 30% Mwt 354.4 Metabolism (rat): hydrolysis of N N ur 5–10% PSA 54.7 A˚ 2 ester, then decarboxylation and log P 2.94 oxidation to lactam, MeO C 2 OH 6-(allylic)-hydroxylation, then oxidation to 6-ketone 299

1/ N t 2 10–16 h V 13 STRYCHNINE F –CL–Rodenticide, central stimulant pb 55–59% Mwt 334.4 H ur 10–20% PSA 32.8 A˚ 2 N H log P 1.59 O O

1/ t 2 0.3–2.5 h V 1 YOHIMBINE N F 5–40% CL 26 Adrenergic α2 antagonist, H pb – Mwt 354.4 mydriatic N H H ur 0.5–1.0% PSA 65.6 A˚ 2 Metabolism: aromatic H log P 2.87 hydroxylation (para to amino MeO C 2 OH group and para to vinyl group)

1/ MeO t 2 168–271 h V – RESERPINE OMe MeO F 40–50% CL – Antihypertensive N MeO H pb 95% Mwt 608.7 Metabolism: ester hydrolysis, 2 N H ur 1% PSA 118 A˚ 4-O-demethylation of H O H O log P 4.45 trimethoxyphenyl MeO C 2 OMe

t1/ 4–12 h V 14 ABECARNIL O 2 MeO F 39–65% CL 11–13 Benzodiazepine agonist, O O pb 94.8% Mwt 404.5 anxiolytic Ph < ˚ 2 N ur 2% PSA 73.4 A Metabolism: O-debenzylation, log P 4.76 then glucuronidation and N H sulfation, ester hydrolysis

1/ HO t 2 19 h (iv) V 11 INTOPLICINE N F –CL18Topoisomerase I inhibitor, HN pb – Mwt 348.4 antineoplastic N ur – PSA 64.2 A˚ 2 log P 4.01 N H

1/ O t 2 17.5 h V 0.9 TADALAFIL F 81% CL 0.6 Phosphodiesterase V inhibitor H N pb 94% Mwt 389.4 for the treatment of erectile N ur Negligible PSA 74.9 A˚ 2 dysfunction N O log P 2.71 Metabolite: methylcatechol H glucuronide

O O

(continued overleaf ) 300 48 Aminoalkylindoles and Indole Alkaloids

1/ H t 2 9.5 h (iv) V 3.3 AG-14699 N F –CL– O PARP inhibitor, oncolytic pb – Mwt 323.4 NH ur – PSA 56.9 A˚ 2 log P 2.62 F N H

1/ O t 2 0.7 h V 0.5 MITOMYCIN C NH 2 F – CL 13.4 Antineoplastic O O pb – Mwt 334.3 Metabolism: elimination of ˚ 2 MeOH to form pyrrole, then H2N OMe ur – PSA 147 A log P −0.30 ring opening of aziridine to N NH aminoalcohol or O aminophosphate

1/ t 2 2h(iv) V 0.06 BIZELESIN Cl HN O F –CL0.7Alkylant, antineoplastic pb – Mwt 815.7 ur – PSA 185 A˚ 2 log P 9.15 HN N N H O HO 2

1/ HO t 2 3–4 h V 0.28–0.36 ALCURONIUM F – CL 1.3–1.4 Muscle relaxant H pb 40% Mwt 666.9 N ˚ 2 H ur 80–85% PSA 46.9 A H log P −2.45 N N H H N H

1/ t 2 4min(iv) V 0.04 INDOCYANINE GREEN F –CL6.8Diagnostic dye N N pb 95% Mwt 754.0 ur – PSA 115.0 A˚ 2 log P 1.38 SO3HSO3H

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; bbb, blood–brain barrier; GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase; PARP, poly(ADP-ribose)polymerase; PGD, prostaglandin; TxA, thromboxane. 301

49 Phenothiazines

The ﬁrst tricyclic antipsychotics were the phenothiazines [1]. Fenethazine (Scheme 49.1) had been tested as an antimalarial during World War II (WWII), and in the late 1940s, researchers at Rhone-Poulenc discovered its antihistaminic properties (H1 antagonism). A small structural modiﬁcation led to the more potent promethazine. Besides showing antihistaminic properties, promethazine was found to prolong the barbiturate-induced sleeping time in rodents.

N N N N

N N N N Cl

S S S S Fenethazine Promethazine Promazine Chlorpromazine t1/2 18 h, F 25% t1/2 8 h, F 17% t1/2 30 h, F 32%

Scheme 49.1 Leads of the antipsychotic chlorpromazine.

Henri Laborit, a military surgeon working in a hospital in Bizerte, Tunisia, often treated his patients with low doses of several drugs simultaneously, instead of administering a large dose of a single drug, in the belief that this would minimize the risk of overdosing. In 1949, while using promethazine to pretreat patients to be anesthetized, he noticed the strong sedating effect of this drug. In 1950, research was initiated at Rhone-Poulenc to discover better phenothiazine-based anxiolytics. An older compound, promazine, prepared as a potential antihistaminic but devoid of H1 antagonism, was chosen as the lead structure. Shortly thereafter, chlorpromazine was prepared, which became the ﬁrst antipsychotic drug (marketed 1952) and a breakthrough in the treatment of schizophrenia [2]. Since then, a huge number of different phenothiazines were developed as neuroleptics for the treatment of psychoses and anxiety. Their mechanism of action is assumed to be central dopamine D2 receptor antagonism. Because

phenothiazines are well tolerated by humans, this substructure has also been used in other types of drugs, for example, in antipyretic arylacetic or arylpropionic acids (Table 49.1).

49.1 Metabolism

Owing to their extensive ﬁrst-pass metabolism, the oral bioavailability of most phenothiazines is low. Moreover, one inherent problem of most phenothiazines is their high afﬁnity for plasma proteins. The free fraction of such drugs can strongly vary with disease or age, and high interindividual variability of pharmacokinetics (PK) is often observed. This complicates the dosing of the drug, and careful monitoring of patients is required. The typical metabolic pathways of phenothiazines are shown in Scheme 49.2.

N-Dealkylation N N-Oxidation

S Hydroxylation Scheme 49.2 Metabolism of Oxidation phenothiazines.

References

1. (a) Marino, M.J. and Knutsen, L.J.S., and Williams, M. (2008) Emerging opportunities for antipsychotic drug discovery in the postgenomic era. J. Med. Chem., 51, 1077–1107; (b) Sneader, W. (2001) Histamine and the classic antihistamines. Drug News Perspect. 14, 618–624. 2. Sneader, W. (2002) The 50th anniversary of chlorpromazine. Drug News Perspect. 5, 466–471. 303

Table 49.1 Phenothiazines and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ ± t 2 11 5h V – PHENOTHIAZINE H F –CL–Anthelmintic N pb – Mwt 199.3 Metabolism: N-glucuronidation, ur – PSA 15.8 A˚ 2 oxidation to sulfoxide, S log P 4 aromatic hydroxylation, then oxidation to quinoneimine

1/ t 2 11 h V – PROTIZINIC ACID N F –CL–Antiinﬂammatory CO H 2 pb – Mwt 315.4 Metabolism: O-demethylation, 2 MeO S ur – PSA 51.5 A˚ oxidation to sulfoxide log P 4.3

t1/ 18±2h V 13.5 PROMETHAZINE N 2 F 25% CL 16 Antihistaminic, antiemetic pb 93% Mwt 284.4 Duration of action: 5±1h 2 N ur 0.6% PSA 8.2 A˚ Metabolism: N-demethylation, log P 4.4 oxidation to sulfoxide S

t1/ 1–2 h V – ETHOPROPAZINE N 2 F <5% (rat) CL – Antiparkinsonian, anticholinergic pb 93% Mwt 312.5 2 N ur – PSA 8.2 A˚ log P 5.2 S

1/ t 2 6h(im) V 3–6 THIAZINAMIUM N F 10% CL 12 Antihistaminic for im dosing pb Mwt 299.5 Metabolism: oxidation to sulfoxide ur 40% (iv) PSA 4.93 A˚ 2 N log P 0.49

t1/ 9±6h V 2–3 PROPIOMAZINE N 2 F 33% CL 3–10 Sedative, hypnotic O pb 81% Mwt 340.5 Metabolism: N-demethylation 2 N ur – PSA 25.2 A˚ log P 4.8 S

(continued overleaf ) 304 49 Phenothiazines

1/ ± t 2 45 26 h V – MEQUITAZINE F –CL–Antihistaminic, does not cross bbb N pb – Mwt 322.5 readily 2 N ur – PSA 8.2 A˚ Metabolism: S-oxidation, aromatic log P 5.1 hydroxylation (para to N) S

1/ t 2 4–14 h V – METHIXENE F –CL–Anticholinergic N pb – Mwt 309.5 Metabolites: desmethyl, N-oxide, ur – PSA 3.2 A˚ 2 sulfoxide, phenols log P 4.7 S

1/ t 2 12 h V – METHDILAZINE N F –CL–Antipruritic, analgesic, pb – Mwt 296.4 antimicrobial N ur – PSA 8.2 A˚ 2 Metabolism: oxidation to sulfoxide log P 4.6 S

1/ ± ± t 2 8 7h(iv) V 8 4PROMAZINE N F 17±9% CL 14±6 Antipsychotic pb 94% Mwt 284.4 Metabolism: N-demethylation, N ur – PSA 8.2 A˚ 2 S-oxidation by CYP1A2 log P 4.4 S

1/ t 2 2–3 h V 3 PROTHIPENDYL N F –CL14Antipsychotic pb – Mwt 285.4 N N ur – PSA 21.1 A˚ 2 log P 3.5 S

1/ ± ± t 2 30 7h V 21 9 CHLORPROMAZINE F 32±19% CL 9±3 Antiemetic, antipsychotic, induces N pb 95–98% Mwt 318.9 hepatic and intestinal mucosa ur <1% PSA 8.2 A˚ 2 enzymes N Cl log P 5.0 Metabolism: N-demethylation, 7-hydroxylation, S-oxidation; active S 1/ metabolites: 7-hydroxy (t 2 ± 1/ . ± . 25 15 h), N-oxide (t 2 6 7 1 4h) 305

1/ ± t 2 10 2h V 11–23 CHLORPROTHIXENE N F 23–64% CL 14–20 Antipsychotic; single isomer (Z) pb >95% Mwt 315.9 Metabolism: S-oxidation to Cl ur – PSA 3.2 A˚ 2 sulfoxide, N-demethylation, log P 5.4 addition of glutathione to alkene S

1/ ∗ t 2 16 h V 6.6 ACEPROMAZINE N F 20%∗ CL – ∗dog O pb >99% Mwt 326.5 Sedative N ur – PSA 25.2 A˚ 2 Metabolism: reduction of ketone to log P 4.3 alcohol S

1/ ± t 2 22 19 h V – TRIFLUPROMAZINE N F –CL–Antipsychotic pb 85–95% Mwt 352.4 N CF3 ur <1% PSA 8.2 A˚ 2 log P 5.3 S

1/ . ± . t 2 4 8 0 6h V – TRIMEPRAZINE N F –CL–Antipruritic pb >90% Mwt 298.5 Metabolism: oxidation to sulfoxide N ur 20% PSA 8.2 A˚ 2 and sulfone, aromatic log P 4.9 hydroxylation, N-dealkylation S

1/ ± t 2 23 8h V 23–42 METHOTRIMEPRAZINE, N F 50–60% CL – LEVOMEPROMAZINE pb Mwt 328.5 Analgesic N OMe ur 1% PSA 17.4 A˚ 2 Metabolites: N-andO-desmethyl, log P 4.9 sulfoxide, glucuronide S

1/ ± t 2 13 3h V – CYAMEMAZINE N F 10–70% CL – Antipsychotic pb – Mwt 323.5 Metabolism: N-demethylation, N CN ur – PSA 32.0 A˚ 2 sulfoxide formation log P 4.6 S

(continued overleaf ) 306 49 Phenothiazines

1/ ± t 2 18 6h V – MELITRACENE N F –CL–Antidepressant; active metabolite: pb 89% Mwt 291.4 N-desmethyl (litracene) ur – PSA 3.2 A˚ 2 log P 4.6

1/ ± H t 2 36–108 h V 52 18 MAPROTILINE N F 37–67% CL 14 Antidepressant pb 88% Mwt 277.4 Metabolism: N-demethylation, ur 3–4% PSA 12.0 A˚ 2 hydroxylation log P 4.0

1/ OH t 2 19 h V 24 LEVOPROTILINE H N F 40% CL 14.6 Antidepressant pb – Mwt 293.4 Metabolism: glucuronidation ur <1% PSA 32.3 A˚ 2 log P 3.13

1/ H t 2 2–3 h V – BENZOCTAMINE N F –CL–Anxiolytic pb – Mwt 249.4 ur – PSA 12.0 A˚ 2 log P 3.5

1/ ± t 2 10–36 h V 21 9 THIORIDAZINE F 25–32% CL 10–14 Antipsychotic 1/ pb 95% Mwt 370.6 Metabolites: sulfoxide (t 2 9–12 h), N N 2 1/ ur <1% PSA 8.2 A˚ sulfone (t 2 9–11 h) S log P 5.6 Further metabolism: aromatic hydroxylation, N-oxidation, SMe N-demethylation; withdrawn in 2005 because of cardiotoxicity

t1/ 6h V – PERAZINE N 2 F 3% CL – Antipsychotic N pb 94–98% Mwt 339.5 Metabolism: N-demethylation 2 N ur – PSA 11.4 A˚ log P 4.3 S 307

t1/ 7±1h V 22–24 PROCHLORPERAZINE N 2 F 13–20% CL – Antipsychotic N pb 91–99% Mwt 373.9 Metabolism: N-demethylation < 2 N Cl ur 1% PSA 11.4 A˚ log P 4.9 S

t1/ 15±5h V – TRIFLUOPERAZINE N 2 F –CL–Antipsychotic N pb 91–99% Mwt 407.5 Metabolite: sulfoxide ur – PSA 11.4 A˚ 2 (t1/ 5.8±1.3h) N CF3 2 log P 5.1 Further metabolism: aromatic S hydroxylation, N-oxidation

t1/ 12 h V 2.7 THIETHYLPERAZINE N 2 F –CL–Antiemetic N pb 60% Mwt 399.6 Metabolism: aromatic 2 N S ur 3% PSA 11.4 A˚ hydroxylation, S-oxidation, log P 5.1 dealkylation S

t1/ 5–30 h V – BUTAPERAZINE N 2 F –CL–Antipsychotic N pb – Mwt 409.6 Metabolites: sulfoxide, sulfone 2 N ur – PSA 52.1 A˚ O log P 4.57 S

t1/ 34 h V – THIOTHIXENE N 2 F –CL–Antipsychotic N pb >99% Mwt 443.6 Metabolism: addition of O O ˚ 2 S ur – PSA 43.9 A glutathione to alkene N log P 4.0 S

1/ ± t 2 4 2h V 4–11 MORICIZINE Antiarrhythmic O F 38% CL 20–42 pb 80–95% Mwt 427.5 Metabolism: hydrolysis of O N ur <1% PSA 72.8 A˚ 2 carbamate and amide, H N N O log P 4.4 O-deethylation to carbamic acid, morpholine cleavage to O 3-aminopropionyl and S hydroxyethylaminopropionyl, oxidation to sulfoxide

(continued overleaf ) 308 49 Phenothiazines

1/ OH t 2 12 h V – PERICYAZINE, F –CL–PROPERICIAZINE N pb – Mwt 365.5 Antipsychotic ur – PSA 52.2 A˚ 2 N CN log P 3.1

1/ OH t 2 11 h V 8.4 PIPOTIAZINE F –CL–Antipsychotic 1/ N pb – Mwt 475.7 Prodrug: palmitate (t 2 12–24 h, O O ur – PSA 65.8 A˚ 2 im) N S N log P 4.3 Metabolism: hydroxylation, sulfoxide formation S

1/ O t 2 5h V – METOPIMAZINE F 22% CL 13 Antiemetic NH2 pb – Mwt 445.6 Metabolism: amide hydrolysis to N ur – PSA 85.4 A˚ 2 carboxylic acid O O log P 2.7 N S

1/ ± OH t 2 10 2h V 10–35 PERPHENAZINE N F 20–40% CL 12–38 Antipsychotic, crosses bbb 1/ N pb 92% Mwt 404.0 Prodrug: enanthate (t 2 2–3 d, im) ur Low PSA 31.6 A˚ 2 Metabolites: sulfoxide, 7-hydroxy N Cl 1/ log P 4.3 (t 2 10–19 h), N-oxide, glucuronide

1/ / OH t 2 12–29 h V 12–24 CLOPENTHIXOL (E Z mixture) N F 50% CL 12.8 Zuclopenthixol (Z isomer, shown) N pb 98% Mwt 401.0 Antipsychotic 2 1/ ur – PSA 26.7 A˚ Prodrug: decanoate (t 2 19 d) Cl log P 4.7 Metabolism: N-dealkylation, S-oxidation S

t1/ 25±9h V 10 FLUPHENAZINE OH 2 N F – CL 12.8 Antipsychotic , 1/ N pb >99% Mwt 437.5 Prodrug: decanoate (Dapotum t 2 ur – PSA 31.6 A˚ 2 132–206 h, im) N CF 3 log P 4.5 Metabolism: aromatic 7-hydroxylation, then S glucuronidation 309

1/ ± ± OH t 2 29 10 h V 15 2 FLUPENTIXOL N F 48–60% CL 6±1 Antipsychotic; mixture of isomers N 1/ pb >95% Mwt 434.5 Prodrug: decanoate (t 2 3–7 d, im) ur – PSA 26.7 A˚ 2 Metabolism: oxidation to sulfoxide, CF3 log P 4.9 addition of glutathione to alkene, S glucuronidation, sulfation

50 Dibenzazepines and Related Tricyclic Compounds

The antidepressant properties of imipramine, a close analog of promazine, were discovered in 1957 by Roland Kuhn, a swiss psychiatrist. Compared to phenothiazines, dibenzazepines (Table 50.1) are less sedating but more mood enhancing and act as norepinephrine and serotonin reuptake inhibitors. Typical metabolic transformations are shown in Scheme 50.1.

N-Dealkylation N N-Oxidation

N Imipramine t1/2 12 h F 39%

Hydroxylation

O NH O NH2 O NH2 2 N N in vivo N + OH

Carbamazepine O Carbamazepine-10,11-epoxide t1/2 15 h F 70−90% t1/2 6 h, F 90%

O NH O NH2 2 N N

HO OH O

Scheme 50.1 Metabolism of dibenzazepines.

Table 50.1 Dibenzazepines and related compounds. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ ± ± t 2 12 5h V 18 3 IMIPRAMINE N F 39±7% CL 15±4 Antidepressant pb 89–91% Mwt 280.4 Metabolism: aromatic and N ur <2% PSA 6.5 A˚ 2 benzylic hydroxylation, log P 4.2 N-demethylation, N-oxidation

1/ t 2 1.8 h (iv) V 1.9 IMIPRAMINE N-OXIDE N O F –CL12Antidepressant N pb – Mwt 296.4 ur – PSA 20.3 A˚ 2 log P 1.71

1/ ± ± H t 2 22 5h V 20 3 DESIPRAMINE N F 38±13% CL 10±2 Antidepressant pb 82±2% Mwt 266.4 Metabolism: aromatic and N ur 2% PSA 15.3 A˚ 2 benzylic hydroxylation log P 3.9

1/ ± O t 2 5 1h V – LOFEPRAMINE N F 10% CL 163 Antidepressant pb 99% Mwt 419.0 Metabolites: desipramine, N ur – PSA 23.5 A˚ 2 2-hydroxydesipramine Cl log P 6.0

1/ ± OH t 2 9 2h V 10 OPIPRAMOL N F 95% CL – Antidepressant, antipsychotic N pb 91% Mwt 363.5 Metabolites: des(hydroxyethyl), ur 7% PSA 31.6 A˚ 2 N-carboxymethyl, N-oxide, N log P 3.1 dibenzazepine

1/ ± t 2 22 14 h V – CYCLOBENZAPRINE F 55% CL 9.8 Muscle relaxant N pb 93% Mwt 275.4 Metabolism: N-demethylation, ur – PSA 3.2 A˚ 2 aromatic hydroxylation, log P 4.9 trans-dihydroxylation of oleﬁn, addition of glutathione to alkene

(continued overleaf ) 312 50 Dibenzazepines and Related Tricyclic Compounds

1/ ± ± t 2 21 5h V 15 3 AMITRIPTYLINE N F 48±11% CL 12±3 Antidepressant pb 95% Mwt 277.4 Metabolism: N-demethylation ur <2% PSA 3.2 A˚ 2 to nortriptyline and benzylic log P 4.2 hydroxylation by CYP2D6

1/ ± ± H t 2 31 13 h V 18 4 NORTRIPTYLINE N F 51±5% CL 7.2±1.8 Antidepressant pb 92±2% Mwt 263.4 Metabolite: ur 2±1% PSA 12.0 A˚ 2 10-hydroxynortriptyline log P 3.9

1/ ± t 2 78 11 h V 21–23 PROTRIPTYLINE H N F 77–93% CL 3–4 Antidepressant pb 91–93% Mwt 263.4 Metabolism: N-oxidation, ur – PSA 12.0 A˚ 2 N-demethylation, log P 4.2 dihydroxylation of alkene, oxidative rearrangement to formylanthracene

1/ H t 2 8h V 7.7 HYDROXYNORTRIPTYLINE N F –CL11Metabolite of nortriptyline pb – Mwt 279.4 ur – PSA 32.3 A˚ 2 log P 3.0

1/ ± ± t 2 17 6h V 20 8DOXEPIN N F 27±10% CL 14±3 Antidepressant pb 78% Mwt 279.4 Active metabolite: ur 0% PSA 12.5 A˚ 2 N-desmethyldoxepin 1/ ± log P 3.9 (t 2 37 15 h) O

1/ ± ∗ t 2 10 2h V – OLOPATADINE N F 57%∗ CL – ∗on intranasal dosing pb 55% Mwt 337.4 Histamine H1 antagonist CO2H ur 60–70%∗ PSA 49.8 A˚ 2 Metabolites: N-desmethyl, log P 2.96 N-oxide O 50 Dibenzazepines and Related Tricyclic Compounds 313

1/ ± t 2 19 5h V 11–78 DOTHIEPIN, DOSULEPIN N F 30% CL 23–63 Antidepressant; mixture of pb – Mwt 295.5 isomers ur 0.5% PSA 3.2 A˚ 2 Metabolism: N-demethylation, log P 4.2 S-oxidation S

1/ O t 2 35 h V – DEMEXIPTILINE N N F –CL– H Antidepressant pb – Mwt 278.4 Metabolism: N-demethylation ur – PSA 33.6 A˚ 2 log P 4.3

1/ t 2 2.4 h V – TIRACIZINE O N H OEt F 34% CL – Antiarrhythmic N pb – Mwt 367.4 Metabolism: carbamate N O ur 3% PSA 61.9 A˚ 2 hydrolysis (to 1/ log P 2.23 des(ethoxycarbonyl), t 2 14 h), N-demethylation

1/ t 2 11–14 h V 1.3–3.4 PIRENZEPINE O N N F 21–33% CL 2.8–3.6 Antiulcerative, muscarinic N N pb 12% Mwt 351.4 acetylcholine M1 antagonist; ur 50% PSA 74.2 A˚ 2 does not cross bbb log P 1.3 Metabolism: N-dealkylation N O H

t1/ 0.8 h V 2.4 AMINEPTINE CO2H 2 HN F –CL32CNS stimulant pb – Mwt 337.5 Metabolism: oxidative ur – PSA 49.3 A˚ 2 degradation of side chain log P 3.98

t1/ 2.5–3.3 h V 0.5–1.2 TIANEPTINE CO2H 2 HN F 99% CL 3.4–5.5 Antidepressant pb 95% Mwt 437.0 Metabolism: oxidative < ˚ 2 Cl ur 3% PSA 95.1 A degradation to C5-aminoacid, NS log P 4.13 little ﬁrst-pass metabolism O O

1/ t 2 20 h V – BUTRIPTYLINE N F –CL–Antidepressant pb >90% Mwt 293.5 Metabolism: N-demethylation ur <2% PSA 3.24 A˚ 2 to norbutriptyline log P 5.30

(continued overleaf ) 314 50 Dibenzazepines and Related Tricyclic Compounds

1/ ± t 2 17 6h V 31 TRIMIPRAMINE N F 41% CL 16 Antidepressant pb 95% Mwt 294.4 Metabolism: N-demethylation, N ur – PSA 6.5 A˚ 2 aromatic hydroxylation log P 4.6

1/ ± N t 2 29–33 h V 34 5 QUINUPRAMINE F 75% CL – Antidepressant pb – Mwt 304.4 N ur – PSA 6.5 A˚ 2 log P 4.98

1/ ± t 2 27 9h V 7–20 CLOMIPRAMINE N F 55±15% CL 6–11 Antidepressant Cl pb 98% Mwt 314.9 Metabolites: N-desmethyl N 2 1/ ± ur 1–3% PSA 6.5 A˚ (t 2 66 11 h), N-oxide, log P 4.8 phenols, benzylic alcohols

1/ t 2 3 h (dog) V – CLOCAPRAMINE O NH2 F 16% CL – Antipsychotic pb – Mwt 481.1 Metabolite: mosapramine N N ur – PSA 52.8 A˚ 2 Cl log P 5.28 N

1/ ± H t 2 15 2h V – MOSAPRAMINE O N F 29±7% CL – Antipsychotic, metabolite pb – Mwt 479.1 of clocapramine N ˚ 2 N ur – PSA 38.8 A Metabolism: aromatic and Cl log P 7.36 benzylic hydroxylation, N oxidation to imidazolone

1/ t 2 1–4 h V – CYPROHEPTADINE N F –CL–Histamine H1 antagonist, pb 96–99% Mwt 287.4 antipruritic ur 0% PSA 3.2 A˚ 2 Metabolites: quaternary log P 5.1 glucuronide, N-desmethyl, epoxide 50 Dibenzazepines and Related Tricyclic Compounds 315

1/ t 2 9–12 h V – AZATADINE N F –CL–Histamine H1 antagonist pb Low Mwt 290.4 ur 20% PSA 16.1 A˚ 2 N log P 3.5

1/ t 2 23 h V – PIZOTYLINE, PIZOTIFEN N F 78% CL – 5-HT antagonist for migraine pb 91% Mwt 295.4 prophylaxis; main metabolite: < 2 1/ ur 1% PSA 31.5 A˚ N-glucuronide (t 2 23 h, log P 2.71 V 1lkg−1)

1/ ± t 2 18 7h V 56 KETOTIFEN ∗ N F 50% CL – 10% of N-desmethyl pb 75% Mwt 309.4 metabolite ur 1%∗ PSA 48.6 A˚ 2 Antiasthmatic log P 2.19 Metabolism: N-demethylation, N-oxidation, S N-glucuronidation, reduction of keto group; active metabolite: O desmethyl

1/ ± H t 2 18 6h V 49 DESLORATADINE N F High CL – Metabolite of loratadine pb 73–87% Mwt 310.8 Metabolism: 3-hydroxylation of ur 0% PSA 24.9 A˚ 2 pyridine, then glucuronidation N log P 3.5

1/ ± ± O O t 2 8 6h V 120 80 LORATADINE F – CL 142±57 Histamine H1 antagonist N pb 97% Mwt 382.9 Duration of action: 24 h ur – PSA 42.4 A˚ 2 Metabolism: hydrolysis of log P 4.6 carbamate N

(continued overleaf ) 316 50 Dibenzazepines and Related Tricyclic Compounds

1/ N t 2 6h V 143 RUPATADINE F 50% CL – Histamine H1 antagonist pb >95% Mwt 416.0 Metabolism: N ur 0% PSA 29.0 A˚ 2 piperidine-N-dealkylation (to log P 6.11 desloratadine), then 3-hydroxylation of pyridine to N 3-hydroxydesloratadine Cl

1/ ± / . ± . t 2 15 5h V F 1 4 0 4 CARBAMAZEPINE O NH2 F 70–90% CL/F 1.3±0.5 Analgesic, anticonvulsant; N pb 74±3% Mwt 236.3 half-life decreases on chronic ur <1% PSA 48.0 A˚ 2 administration log P 2.8 Metabolite: 10,11-epoxide

1/ / . ± . O NH2 t 2 6h V F 1 1 0 2 CARBAMAZEPINE-10,11- F 90±11% CL/F 1.7±0.3 EPOXIDE N pb 50% Mwt 252.3 Metabolite of carbamazepine ur <1% PSA 58.9 A˚ 2 log P 2.5 O

t1/ 2h V 0.7−0.8 OXCARBAZEPINE O NH2 2 F –CL–Anticonvulsant N pb 40% Mwt 252.3 Metabolites: < ˚ 2 1/ ur 1% PSA 63.4 A 10-hydroxycarbamazepine (t 2 log P 2.5 9 h), glucuronide thereof, O 10,11-dihydroxy

1/ ∗ . ∗ O NH t 2 9–13 h V 0 8 ESLICARBAZEPINE Acetate 2 ∗ ∗ F >90% CL 0.9 ∗eslicarbazepine on oral dosing ∗ N pb 40% Mwt 296.3 of ester; prodrug of ∗ ur 60% PSA 72.6 A˚ 2 eslicarbazepine, sodium O log P 1.70 channel blocker O Metabolism: glucuronidation

t1/ 8–12 h V 5.2 EPINASTINE N NH 2 2 F 40% CL 14 Antihistaminic (racemic; N pb 64% Mwt 249.3 eye-drops); does not cross bbb, ur 55% PSA 41.6 A˚ 2 little metabolism log P 2.9 50 Dibenzazepines and Related Tricyclic Compounds 317

1/ ± t 2 14 3h V 16 MIANSERIN N F 20% CL 9.9±1.2 Antidepressant pb 90–95% Mwt 264.4 Metabolism: N-demethylation, N ur – PSA 6.5 A˚ 2 hydroxylation log P 3.6

1/ t 2 13–40 h V 4.8 MIRTAZAPINE N F 48–50% CL 7.4 Antidepressant pb 85% Mwt 265.4 Metabolism: pyridine N < ˚ 2 N ur 4% PSA 19.4 A hydroxylation (para to log P 2.7 piperazine), N-demethylation, N-oxidation

1/ HN t 2 8.3 h V 0.6–1.4 METAPRAMINE F – CL 17–27 Antidepressant pb – Mwt 238.3 Metabolism: N-demethylation ur – PSA 15.3 A˚ 2 N log P 3.4

1/ O H t 2 25–45 h V 1.2 NEVIRAPINE ± N F 93 9% CL 0.3 Antiviral (HIV) pb 60% Mwt 266.3 Metabolism: hydroxylation and ur <3% PSA 58.1 A˚ 2 oxidation of CH to CO H, N 3 2 N N log P 1.84 hydroxylation of pyridines, then glucuronidation

1/ t 2 4–5 h V 4.6 DIBENZEPIN N F 25% CL – Antidepressant O pb 80% Mwt 295.4 Metabolism: demethylation at N ur 1% PSA 30.2 A˚ 2 side chain log P 3.0 N

1/ t 2 9.4 h (iv) V – DIAZEPINOMICIN F –CL–Antibacterial O pb 67% Mwt 462.6 Metabolite: glucuronide N ur – PSA 93.0 A˚ 2 OH log P 8.11 N H OH HO

(continued overleaf ) 318 50 Dibenzazepines and Related Tricyclic Compounds

1/ ± ± t 2 21 9h V 109 59 ZOTEPINE N F 7–13% CL 77±70 Atypical antipsychotic O pb 97% Mwt 331.9 Metabolites: N-desmethyl, ur – PSA 12.5 A˚ 2 N-oxide, sulfoxide, phenols Cl log P 5.5 S

1/ ± . ± . t 2 12 4h V 5 4 3 5CLOZAPINE N F 55±12% CL 6.1±1.6 Antipsychotic pb >95% Mwt 326.8 Metabolism: N-demethylation, N < ˚ 2 aromatic hydroxylation, N ur 1% PSA 30.9 A Cl log P 3.94 oxidative degradation of piperazine ring N H

1/ ± t 2 15 3h V – LOXAPINE N F 30% CL – Anxiolytic pb – Mwt 327.8 Metabolism: aromatic N ur – PSA 32.5 A˚ 2 hydroxylation, N-demethylation N Cl log P 4.2 to amoxapine O

1/ NH t 2 8–11 h V –AMOXAPINE F –CL15Antidepressant N pb – Mwt 313.8 Metabolite of loxapine N ur Negligible PSA 41.3 A˚ 2 Metabolites: 7- and 1/ Cl log P 3.7 8-hydroxyamoxapine (t 2 6and 30 h) O

1/ t 2 24 h V 20–25 ASENAPINE ∗ N F <2%∗ CL 13 35% buccal H H pb 95% Mwt 285.8 Antipsychotic ur Low PSA 12.5 A˚ 2 Metabolites: desmethyl, Cl log P 4.31 N-glucuronide, O N-carbamoylglucuronide

1/ t 2 27–39 h V 10–22 OLANZAPINE N F 60–80% CL 4.5–5.1 Antipsychotic pb 93% Mwt 312.4 Metabolism: N-demethylation, N ur 7% PSA 35.2 A˚ 2 hydroxylation of CMe N log P 3.5

N S H 50 Dibenzazepines and Related Tricyclic Compounds 319

1/ ± t 2 6–7 h V 10 4 QUETIAPINE N O F 9±4% CL – Atypical antipsychotic OH pb 83% Mwt 383.5 Metabolism: piperazine N ur 1–5% PSA 48.8 A˚ 2 N-dealkylation (to N 1/ log P 3.5 desalkylquetiapine, t 2 9–12 h)

51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’)

Five adrenaline receptors have been identified: two α- and three β-receptors. α-Adrenoceptor antagonists were developed as early as 1933 (piperoxan), and the more potent tolazoline (early 1940s) and phentolamine (1950s) are still used today as nasal decongestants by virtue of their vasoconstricting properties. In 1958, James Black joined the pharmaceutical division of ICI and attempted to develop a β-adrenaline antagonist for the treatment of angina pectoris. The result of this research was the β-blocker propranolol, launched in 1965. Since then, a large number of 3-aryloxy-2-hydroxypropylamines were developed and marketed for use in humans, mainly as antianginals, antihypertensives, antiarrhythmics, and, topically, for the treatment of glaucoma (lowering the intraocular pressure). A comparison of the structures and pharmacokinetic (PK) properties of these compounds gives useful insight into how PK properties may be influenced by structural modifications and which chemical substructures are acceptable for a drug. The 3-aryloxy-2-hydroxypropylamine substructure is essential for biological activity and conserved in most of these compounds. Half-lives and oral bioavailabilities of β-blockers range from 1 to 22 h and from 5 to 100%, respectively, and β-blockers include highly lipophilic compounds, which readily cross the blood–brain barrier (such as propranolol), and more hydrophilic molecules, which are unable to attain high concentrations in the central nervous system (CNS) (e.g., atenolol).

51.1 Metabolism

The hydrophilic 2-hydroxypropylamine substructure neither is metabolized by specific hormone-degrading enzymes nor is a good substrate of the less substrate- specific liver enzymes (CYP). Therefore, metabolism of β-blockers occurs mostly at the lipophilic aryloxy group. For instance, propranolol, alprenolol, penbutolol, and tertatolol are mainly hydroxylated at the 4-position of the aryloxy group (by liver enzymes) to yield monoalkylated hydroquinones (Scheme 51.1). Other metabolic pathways include dealkylation of the aryloxy and amino groups. Thus, first-pass

OH OH OH H Metabolism H O N O N + O NH2

HO Propranolol t 1/2 4 h, F 26% ++OH OH

compare to:

OH OH H H O N O N O O

N H Practolol Levobunolol t 1/2 5–13 h, F 100% t 1/2 20 h, F 80%

Scheme 51.1 Metabolism of propranolol.

Table 51.1 3-Aryloxy-2-hydroxypropylamines (β-adrenergic antagonists; antianginals, antihypertensives, antiarrhythmics, and antiglaucoma agents). V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ . ± . t 2 2 0 0 3h V –BUPRANOLOL OH H F <10% CL – Metabolism: oxidation of ArMe to O N pb 80–90% Mwt 271.8 ArCO2H ur <10% PSA 41.5 A˚ 2 Cl log P 3.4

1/ t 2 3h V – XIBENOLOL OH H F –CL–Metabolism: aromatic O N 1/ pb – Mwt 237.3 4-hydroxylation (t 2 3 h), 3-CH3 2 ur 1% PSA 41.5 A˚ hydroxylation, oxidation of 3-CH3 log P 2.6 to CO2H

1/ OH t 2 2–5 h V 2.3–7.2 L-PENBUTOLOL H O N F 90–95% CL 16.6 Metabolites: glucuronide, pb 80–98% Mwt 277.4 4-hydroxyphenoxy ur 4–6% PSA 41.5 A˚ 2 log P 3.1

(continued overleaf ) 322 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’)

1/ t 2 2–3 h V 3 ALPRENOLOL OH H F 10–15% CL 1.2 Metabolism: glucuronidation, O N pb 80–90% Mwt 249.4 N-dealkylation, then ur <1% PSA 41.5 A˚ 2 N-methylation, 4-hydroxylation, log P 2.6 oxidative degradation

t1/ 1–2 h V 1.6 OXPRENOLOL OH 2 H F 24–60% CL – Metabolism: glucuronidation, O N pb 70–80% Mwt 265.4 aromatic 4- and 5-hydroxylation ur 2–5% PSA 50.7 A˚ 2 O log P 2.1

1/ OH t 2 6–8 h V 2–3 CETAMOLOL H O N F – CL 4–6 Metabolism: aromatic pb – Mwt 310.4 hydroxylation, N-demethylation, O 2 O ur 30–50% PSA 79.8 A˚ O-dealkylation, oxidative HN log P 1.36 deamination to aryloxyacetic acid

1/ . ± . OH t 2 2 1 0 3h V – MOPROLOL H O N F –CL– pb – Mwt 239.3 2 OMe ur – PSA 50.7 A˚ log P 1.42

1/ . ± . . ± . t 2 3 3 1 0h V 0 73 0 28 VILOXAZINE O F 85±14% CL 2.0±0.2 Antidepressant O NH pb 88±3% Mwt 237.3 Metabolism: aromatic 4- and ur 12–15% PSA 39.7 A˚ 2 5-hydroxylation O log P 1.3

1/ t 2 13 h V 0.92 REBOXETINE O O F 95% CL 0.41–0.53 Antidepressant O NH pb 92–97% Mwt 313.4 Metabolism: O-deethylation, Ph ur 8–9% PSA 39.7 A˚ 2 aromatic hydroxylation (para to log P 2.45 both alkoxy groups)

1/ t 2 2.2 h (rat) V – INDELOXAZINE O F –CL–Antidepressant, nootropic O NH pb – Mwt 231.3 Metabolism (rat): dihydroxylation ur – PSA 30.5 A˚ 2 of alkene, N-acetylation, oxidative log P 1.79 degradation of morpholine ring

1/ . ± . . ± . t 2 3 9 0 4h V 4 3 0 6 PROPRANOLOL OH H F 26±10% CL 16±5 Metabolism: 4-, 2-, 5-, and O N pb 87±6% Mwt 259.4 7-hydroxylation of naphthyl, ur <1% PSA 41.5 A˚ 2 N-deisopropylation log P 3.0 323

1/ ± t 2 9 7h V 0.4–0.7 TERTATOLOL S OH H F 60% CL – Metabolism: aromatic O N pb 94% Mwt 295.5 4-hydroxylation, benzylic ur <1% PSA 41.5 A˚ 2 hydroxylation, sulfoxide formation log P 3.2

t1/ 3.7 h V 5.6 NIPRADILOL O 2 O N O OH F 35% CL – Metabolism: hydrolysis of nitrate to 2 H O N pb 34% Mwt 326.5 alcohol, N-deisopropylation ur 6.3% PSA 105.8 A˚ 2 log P 2.2

1/ t 2 20 h V 5.5 LEVOBUNOLOL OH H F 80% CL 0.16 Metabolism: reduction of keto O N O pb – Mwt 291.4 group to alcohol ur 14% PSA 58.6 A˚ 2 log P 2.6

1/ N t 2 1–3 h V 0.67 NICAINOPROL F 70% CL 3.6 Antiarrhythmic pb 70% Mwt 369.5 ˚ 2 N O OH ur 9% PSA 74.7 A H O N log P 1.58

t1/ 6–8 h V 4.1 CARTEOLOL O 2 OH F 85% CL 8–10 Metabolism: benzylic H HN O N pb 15% Mwt 292.4 hydroxylation, glucuronidation ur 50–70% PSA 70.6 A˚ 2 log P 2.0

1/ ± . ± . OH t 2 16 2h V 1 9 0 2 NADOLOL ± . ± . HO F 34 5% CL 2 9 0 6 OH H pb 20±4% Mwt 309.4 O N ur 73±4% PSA 82.0 A˚ 2 log P 1.2

1/ . ± . . ± . t 2 3 6 0 6h V 2 3 0 9PINDOLOL F 75±9% CL 8.3±1.8 Metabolism: glucuronidation, OH H pb 51±3% Mwt 248.3 aromatic hydroxylation (to HN O N ur 54±9% PSA 57.3 A˚ 2 indolin-2-one and 3-hydroxy), then log P 2.0 sulfation, oxidative ring scission to anthranilic acid, oxidative deamination (continued overleaf ) 324 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’)

1/ . ± . t 2 4 0 1 5h V 5.7 MEPINDOLOL OH F >95% CL – Prodrug of mepindolol: H HN O N pb 50–60% Mwt 262.4 O-benzoylmepindolol (bopindolol; 2 1/ ur 2% PSA 57.3 A˚ t 2 mepindolol on oral dosing of log P 2.2 bopindolol: 6–10 h)

1/ t 2 2.4 h V 2.6–3.4 PRENALTEROL OH F 45–55% CL 21 Cardiotonic H O N pb <5% Mwt 225.3 Metabolism: O-sulfation, ur 30–60% PSA 61.7 A˚ 2 O-glucuronidation, oxidative HO log P 1.3 deamination to 4-(hydroxyphenoxy)lactic acid

1/ ∗ . ∗ OH t 2 2.5–4.0 h V 3 5 METIPRANOLOL H ∗ . ∗ ∗ O N F 50% CL 15 7 rapid deacetylation in vivo. values ∗ O pb 70% Mwt 309.4 for desacetyl metabolite on oral ∗ 2 O ur 12% PSA 67.8 A˚ dosing of metipranolol log P 2.28

OH t1/ 5–13 h V 1.6 PRACTOLOL H 2 O N F 100% CL 0.14 Metabolism: deacetylation, then O pb 32% Mwt 266.3 N-hydroxylation of aniline N ur >90% PSA 70.6 A˚ 2 H log P 1.0

1/ ± O t 2 10 2h V –DIACETOLOL OH H F 30–43% CL 16±1 Metabolite of acebutolol (see below) O N O pb 6–9% Mwt 308.4 ur 65% PSA 87.7 A˚ 2 N H log P 0.85

1/ . ± . . ± . O t 2 2 7 0 4h V 1 2 0 3 ACEBUTOLOL OH H F 37±12% CL 6.8±0.8 Metabolism: hydrolysis of amide, O N O pb 26±3% Mwt 336.4 then acetylation to diacetolol (see ur 30% PSA 87.7 A˚ 2 above) N H log P 2.3

OH t1/ 4–6 h V 4.5 CELIPROLOL H 2 O N F 55–74% CL – Metabolism: N-deethylation O pb 25–30% Mwt 379.5 N N ur 12–18% PSA 90.9 A˚ 2 H log P 2.7 O 325

t1/ 9–11 h V 3.3 TALINOLOL OH 2 H F 52% CL 4.9 O N Metabolism: hydroxylation of O pb 60% Mwt 363.5 cyclohexyl group 2 N N ur 28% PSA 82.6 A˚ H H log P 3.7

1/ O t 2 7–10 h V 3–8 BUTOFILOLOL OH H F – CL 10–18 Antihypertensive O N pb – Mwt 311.4 ur 4% PSA 58.6 A˚ 2 F log P 3.31

1/ . ± . . ± . t 2 5 5 2 1h V 3 6 2 1 PROPAFENONE Ph O OH F 5–50% CL 17±8 CYP2D6 substrate H O N pb 85–95% Mwt 341.5 Metabolism: N-depropylation, ur <1% PSA 58.6 A˚ 2 aromatic hydroxylation (para to OR) log P 3.5

t1/ 1.5 h (iv) V 1.2 (S)-DIPRAFENONE Ph O 2 OH F 11–33% CL 11 Metabolism: aromatic H O N pb 98% Mwt 369.5 hydroxylation (para to OR) ur – PSA 58.6 A˚ 2 log P 4.12

1/ t 2 14–22 h V 4.9–9.8 BETAXOLOL OH H F 89±5% CL 4.7 Metabolism: oxidative deamination O N pb 55% Mwt 307.4 to aryloxyacetic acid, benzylic ur 15% PSA 50.7 A˚ 2 hydroxylation O log P 2.8

t1/ 11±3h V 3.2±0.5 BISOPROLOL OH 2 H F 91±10% CL 3.7±0.7 Metabolism: O-deisopropylation O N O pb 35±5% Mwt 325.5 O ur 63±8% PSA 60.0 A˚ 2 log P 2.3

t1/ 3.2±0.2h V 4.2±0.7 METOPROLOL OH 2 H F 38±14% CL 15±3 O N Metabolism: benzylic pb 11±1% Mwt 267.4 hydroxylation, O-demethylation ur 10±3% PSA 50.7 A˚ 2 O log P 2.0

1/ OH t 2 20 h V 9 RO 31-1118 H O N F 57% CL – S-enantiomer: ﬂusoxolol pb – Mwt 391.5 2 O ur – PSA 60.0 A˚ O log P 3.7

(continued overleaf ) 326 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’)

1/ . ± . t 2 5–10 min V 1 9 1 3 ESMOLOL OH H F – CL 170±70 Metabolism: ester hydrolysis O O O N pb 41–55% Mwt 295.4 ur <1% PSA 67.8 A˚ 2 log P 1.92

t1/ 6±2h V 0.95±0.15 ATENOLOL OH 2 H F 56±30% CL 1.2–2.1 Metabolism: hydroxylation of O N O pb 5–16% Mwt 266.3 benzylic CH2 ur >90% PSA 84.6 A˚ 2 H N 2 log P 0.7

1/ t 2 6h V 1.1 PAFENOLOL O OH H F 27–46% CL 4.5 Metabolism: benzylic hydroxylation O N N NH pb – Mwt 337.5 H ur 56% (iv) PSA 82.6 A˚ 2 log P 1.66

1/ ± . ± . O t 2 4 1h V 2 1 0 8 TIMOLOL F 30–50% CL 7.3±3.3 Metabolism: oxidation of OH ± N H pb 60 3% Mwt 316.4 morpholine to lactam, O N ur 15% PSA 79.8 A˚ 2 N-(2-hydroxyethyl)glycolamido, and N log P 1.1 to 2-hydroxyethylamino group, S N hydroxylation of tert-butyl

1/ OH t 2 8h V 10.9 CARAZOLOL H < O N F 10% CL – Metabolism (dog): pb 81% Mwt 298.4 O-glucuronidation, oxidative ur <0.2% PSA 57.3 A˚ 2 deamination, aromatic HN log P 3.3 hydroxylation

t1/ 4±2h V 1.5±0.3 CARVEDILOL OH 2 H . ± . Antihypertensive O N F 25% CL 8 7 1 7 O pb 95% Mwt 406.5 Metabolism: glucuronidation, OMe ur <2% PSA 75.7 A˚ 2 O-demethylation, aryloxy HN log P 3.6 hydroxylation, carbazole 2-hydroxylation

1/ t 2 2.3–3.6 h V 2.6 ALMOKALANT OH O F 55% CL 11±1 Antiarrhythmic O N S pb 20% Mwt 352.5 Metabolism: N-dealkylation, ur 10% PSA 92.8 A˚ 2 O-glucuronidation, oxidation to NC log P 1.79 sulfone, CH3 hydroxylation of propyl chain 327

1/ ± ± OH O t 2 17 9h V 6 3EPANOLOL H ± ± O N F 10 8% CL 28 12 Antihypertensive, antianginal N H pb 50% Mwt 369.4 2 CN ur 1–26% PSA 114.6 A˚ log P 0.92

1/ ± t 2 16 3h V 1.1–2.0 XAMOTEROL OH O H F 5% CL 3.7 Metabolism: O-sulfation O N N N pb 3% Mwt 339.4 H O ˚ 2 HO ur 73% PSA 103.3 A log P 0.38

OH O 1/ H t 2 2–4 min V – LANDIOLOL O N F –CL– N N Metabolism: ester hydrolysis H pb – Mwt 509.6 O O ur – PSA 128 A˚ 2 O O log P 0.80 O

1/ O t 2 2.6 h V 4 TOLAMOLOL F –CL14 OH NH Metabolism: aromatic H 2 O N pb 91% Mwt 344.4 4-hydroxylation O ur – PSA 93.8 A˚ 2 log P 1.7

t1/ 1–2 h V 1.3–2.8 RANOLAZINE H 2 N F 35–50% CL 10 Antianginal OH N Metabolism: hydroxylation, O N O pb 63% Mwt 427.5 ur <5% PSA 74.3 A˚ 2 glucuronidation, N-dealkylation, OMe log P 1.31 O-demethylation, O-dearylation, amide hydrolysis

1/ . ± . t 2 5 4 3 2h V – NAFTOPIDIL F 7–30% CL 11±1.6 Antihypertensive OH N pb 95–97% Mwt 392.5 Metabolism: aromatic O N OMe ur – PSA 45.2 A˚ 2 hydroxylation, piperazine log P 4.1 dealkylation, O-demethylation

1/ t 2 25 h (iv) V 268–350 ZOSUQUIDAR F F – CL 108–158 P-glycoprotein inhibitor, adjunct F pb – Mwt 527.6 antineoplastic OH N ur – PSA 48.8 A˚ 2 Metabolism: N-oxidation and N O N log P 4.30 hydroxylation of quinoline

(continued overleaf ) 328 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; ‘‘β-Blockers’’)

1/ ± t 2 18 10 h V – SABELUZOLE N OH S F –CL5.1Nootropic O N N pb 99% Mwt 415.5 Metabolism: 6-hydroxylation of ur <0.5% PSA 77.1 A˚ 2 benzothiazole, glucuronidation F log P 4.26

1/ t 2 15–24 h V 2.5–3.4 LUBELUZOLE N OH S F – CL 2.2–3.9 Neuroprotectant F O N N pb >99% Mwt 433.5 Metabolism: 6-hydroxylation of ur – PSA 77.1 A˚ 2 benzothiazole, glucuronidation F log P 4.69

1/ ± O H t 2 14 5h V –ADIMOLOL N F 33–52% CL 12±6 Antihypertensive N pb – Mwt 474.0 OH H ur – PSA 79.3 A˚ 2 O N log P 4.20

1/ t 2 10–50 h V 10–39 NEBIVOLOL OH OH H F 12–96% CL 12.3 Metabolism: aromatic and benzylic O N O pb 98% Mwt 405.4 hydroxylation, N-dealkylation, H H < ˚ 2 F F ur 1% PSA 71 A glucuronidation log P 3.1

1/ t 2 1.5–2.0 h V 1.5 BEVANTOLOL F 60% CL 4.4–6.9 Antianginal, antihypertensive, OH H pb >95% Mwt 345.4 antiarrhythmic O N OMe ur <1% PSA 60.0 A˚ 2 Metabolism: aromatic OMe log P 3.00 4-hydroxylation, oxidation of CCH3 to CCH2OH and CCO2H, then glucuronidation

52 Opiates

Enkephalins, endorphins, and dynorphins are the three classes of known endogenous opioid peptides [1]. The N-terminus of all these peptides is H-Tyr-Gly-Gly-, and morphine and related strong analgesics are mimetics of this peptide fragment (Scheme 52.1).

HO HO

O O N O NH H H 2 H N NH HO R N H O Morphine Common N-terminus of opioid peptides t 1/2 1.9 h, F 24%

Scheme 52.1

The opiate and opioid peptide binding receptors have been classiﬁed into three subtypes: µ-, κ-, and δ-receptors. These are mainly expressed in the central and peripheral nervous system (e.g., in the spinal cord) and in the ileum. Morphine, the main alkaloid of opium, is a µ-receptor agonist and its main effects in humans are analgesia, drowsiness, changes in mood, and mental clouding. Numerous analogs of morphine have been prepared with the aim of identifying less addicting and less constipating drugs, but these efforts have largely been unsuccessful. Opiates remain the treatment of choice for strong pain and, at low dose, for the treatment of cough. Table 52.1 includes only those compounds that are structurally related to morphine.

Reference

1. (a) Trescot, A.M., Datta, S., Lee, M., and Hansen, H. (2008) Opioid pharmacology. Pain Physician, 11, S133–S153; (b) Sneader, W. (1998) The discovery of heroin. Lancet, 352, 1697–1699.

Table 52.1 Opiates and related compounds. V in l kg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ MeO t 2 4–8 h V 0.4–0.8 VERNAKALANT F 20% CL – Treatment of atrial ﬁbrillation MeO O pb 53–63% Mwt 349.5 Metabolism: O-demethylation OH N ur – PSA 51.2 A˚ 2 log P 2.40

1/ MeO t 2 5–6 h V 2.9–3.7 TRAMADOL F 70–90% CL 6.7–8.3 Analgesic, crosses bbb; active pb 20% Mwt 263.4 metabolite: O-desmethyl HO 2 1/ ur 10–30% PSA 32.7 A˚ (t 2 5–10 h); other N log P 2.32 metabolites: N-desmethyl

1/ t 2 – V 3.7 TILIDINE F 8±5% CL 18±4 Analgesic, racemic pb 79% Mwt 273.4 Metabolism: N-demethylation EtO2C N ur 0.2% PSA 29.5 A˚ 2 to nortilidine log P 4.62

1/ ± t 2 3–5 h V 3 1 NORTILIDINE F 99%∗ CL 12±2 ∗on oral administration of pb 25% Mwt 259.3 tilidine; metabolite of tilidine EtO2C H N ur 2–3% PSA 38.3 A˚ 2 Metabolism: N-demethylation 1/ log P 4.75 to bisnortilidine (t 2 5h)

1/ ± / HO t 2 3 1h V F 11.2 KETOBEMIDONE F 34±16% CL/F 26 Analgesic; Metabolism: pb – Mwt 247.3 glucuronidation, ˚ 2 O ur 3–10% PSA 40.5 A N-demethylation, N log P 0.80 N-oxidation, aromatic 4-hydroxylation

1/ HO t 2 10–17 h V 0.3–0.6 ALVIMOPAN F 1–19% CL 6 Opiate antagonist; pb 80–90% Mwt 424.5 does not cross bbb ur 2% PSA 89.9 A˚ 2 Metabolism: amide hydrolysis N log P 3.38 H HN O

CO2H 331

1/ ∗ HO t 2 11–15 h V 10–13 LEVORPHANOL F – CL 10.5 ∗iv pb 40% Mwt 257.4 Analgesic ur 5% PSA 23.5 A˚ 2 Metabolism: glucuronidation, N log P 3.26 N-demethylation H

1/ HO t 2 1h V – LEVALLORPHAN F Low CL – Opioid antagonist pb – Mwt 283.4 Metabolism: glucuronidation, ur – PSA 23.5 A˚ 2 N-deallylation N H log P 3.85

1/ MeO t 2 3–6 h V – LEVOMETHORPHAN F – CL – Analgesic pb – Mwt 271.4 Metabolism: O-demethylation ur – PSA 12.5 A˚ 2 to levorphanol N H log P 3.89

1/ ∗ MeO t 2 1–4 h V 5.0–6.4 DEXTROMETHORPHAN F 11% CL – ∗dog pb – Mwt 271.4 Antitussive ur – PSA 12.5 A˚ 2 Metabolism: O-demethylation N log P 3.89 to dextrorphanol (t1/ 3–4 h), H 2 N-demethylation

1/ HO t 2 2.5–5.8 h V 4–13 BUTORPHANOL F 5–17%∗ CL 41–43 ∗intranasal: 48–70% pb 83% Mwt 327.5 Analgesic, antiussive; ur 2–10% PSA 43.7 A˚ 2 crosses bbb N log P 3.54 Metabolism: hydroxylation of OH cyclobutyl, N-dealkylation

1/ HO t 2 2–3 h V 3–4 HYDROMORPHONE F 22–26% CL 15–28 Analgesic, narcotic pb 8–19% Mwt 285.3 Metabolism: glucuronidation, O ur 6% PSA 49.8 A˚ 2 reduction of ketone to N log P 2.13 alcohol H H O (continued overleaf ) 332 52 Opiates

1/ MeO t 2 4–6 h V 3.3–4.7 HYDROCODONE F 60–70% CL 9.6 Antiussive pb – Mwt 299.4 Metabolism: N- and O ur 12% PSA 38.8 A˚ 2 O-demethylation, reduction N H log P 2.57 of ketone to alcohol, H glucuronidation O

1/ MeO t 2 3.3–4.5 h V 1.0–1.3 DIHYDROCODEINE F 12–34% CL 4 Analgesic, antiussive pb – Mwt 301.4 Metabolism: O- and O ur 13–22% PSA 41.9 A˚ 2 N-demethylation, N log P 0.61 glucuronidation H H HO

1/ . ± . / . ± . MeO t 2 2 9 0 7h V F 2 6 0 3CODEINE F 50±7% CL/F 11±2 Analgesic, antiussive pb 7% Mwt 299.4 Metabolism: O- and O ur <10% PSA 41.9 A˚ 2 N-demethylation, N log P 1.39 glucuronidation H H HO

1/ ± O t 2 37 4h V 36–49 PHOLCODINE N F High CL 10 Antiussive O pb 26% Mwt 398.5 Metabolism: O ur 30–50% PSA 54.4 A˚ 2 N-demethylation, N log P 0.56 N-dealkylation of morpholine H H (to hydroxyethylmorphine) HO

1/ . ± . . ± . HO t 2 1 9 0 5h V 3 3 0 9 MORPHINE F 24±12% CL 24±10 Analgesic, narcotic; active pb 35±2% Mwt 285.3 metabolite: 6-glucuronide O ± 2 1/ . ± . ± ur 4 5% PSA 52.9 A˚ (t 2 4 5 1 5h,ur14 7%) N log P 0.87 H H HO 333

1/ . ± . O t 2 3min(iv) V 1 0 0 5HEROIN, F <35% CL 175±74 DIACETYLMORPHINE O pb – Mwt 369.4 Prodrug of morphine O ur Negligible PSA 65.1 A˚ 2 Metabolites: O N 1/ H log P 1.58 6-monoacetylmorphine (t 2 H 20 min), morphine, O 6 6-glucuronide

1/ MeO t 2 2–6 h V 2–4 OXYCODONE F 60–87% CL 11–19 Analgesic pb 38–45% Mwt 315.4 Metabolism: N- and O ur 13–19% PSA 59.0 A˚ 2 O-demethylation, N log P 1.59 glucuronidation H OH O

1/ . ± . HO t 2 1 1 0 6h V 2.1 NALOXONE F 2% CL 22 Narcotic antagonist pb 32–46% Mwt 327.4 Metabolism: glucuronidation, O ur Negligible PSA 70.0 A˚ 2 N-dealkylation, reduction of N log P 1.78 ketone to alcohol H OH O

1/ . ± . ± HO t 2 2 7 1 0h V 19 5 NALTREXONE F 5–40% CL 48±6 Narcotic antagonist pb 21% Mwt 341.4 Metabolism: glucuronidation, O ur <1% PSA 70.0 A˚ 2 N-dealkylation, reduction of N 1/ log P 2.05 ketone to alcohol (t 2 9h) H OH O

1/ HO t 2 8–11 h V 8.2 NALMEFENE F 40–50% CL 15 Narcotic antagonist pb 34–45% Mwt 339.4 Metabolism: glucuronidation, O ur 3–8% PSA 52.9 A˚ 2 N-dealkylation N log P 1.63 H OH

1/ . ± . . ± . HO t 2 2 3 1 2h V 3 8 1 1 NALBUPHINE F 16±8% CL 22±5 Analgesic, narcotic pb 50% Mwt 357.4 Metabolism: N-dealkylation, O ur 4±2% PSA 73.2 A˚ 2 oxidation of secondary alcohol N log P 1.22 to ketone H OH HO (continued overleaf ) 334 52 Opiates

1/ HO t 2 2–7 h V 1–5 BUPRENORPHINE F 30%∗ CL 13–19 ∗sublingual pb 96% Mwt 467.6 Analgesic O ur Negligible PSA 62.2 A˚ 2 Metabolism: N-dealkylation, N log P 2.83 glucuronidation H MeO H OH

1/ HO t 2 2.0–2.3 h V 1.1–2.6 METHYLNALTREXONE F Low CL 6.5–8.6 Narcotic antagonist, does not pb 11–15% Mwt 356.4 cross bbb; Metabolism: O ur 50% (sc) PSA 66.8 A˚ 2 reduction of ketone to alcohol, N H log P −2.63 N-demethylation (<0.06% of OH O dose)

1/ ± ∗ . ± . HO t 2 41 15 min V 1 6 0 5APOMORPHINE F 2% CL 40±15 ∗iv HO pb 94% Mwt 267.3 Emetic H ur <1% PSA 43.7 A˚ 2 Metabolism: N log P 1.70 N-demethylation, O-sulfation, O-glucuronidation

1/ MeO t 2 5–8 h V 2.6 GALANTAMINE F 85–100% CL 5.7 Cholinesterase N pb 17–18% Mwt 287.4 inhibitor O ur 18–25% PSA 41.9 A˚ 2 Metabolism (by CYP2D6 H log P −0.05 and CYP3A4): N- and HO O-demethylation, N-oxidation

53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils)

The endogenous peptide angiotensin II strongly raises arterial blood pressure by inhibiting the excretion of water and Na+ by the kidneys and by increasing the total peripheral vascular resistance. In the 1960s, some peptides present in viper venom were found to inhibit angiotensin converting enzyme (ACE). One of these peptides (teprotide, pyrGlu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro-OH) turned out to lower blood pressure more consistently than peptidic angiotensin II antagonists such as saralasin (1-sarcosine,8-isoleucine-angiotensin II). This discovery led to the search for orally available ACE inhibitors as antihypertensives. Angiotensin II is the product of the ACE-mediated cleavage of angiotensin I, which has only about 1% of the blood-pressure-increasing potency of angiotensin II (Scheme 53.1). Angiotensin III, which results from the degradation of angiotensin II by an aminopeptidase, is only 25% as potent as angiotensin II. The angiotensin receptors (AT1 and AT2) are G-protein-coupled receptors (GPCRs) located at the surface of cells in various tissues.

Angiotensinogen H2N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-R

renin

Angiotensin I H2N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-OH ACE

Angiotensin II H2N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH aminopeptidase

Angiotensin III H2N-Arg-Val-Tyr-Ile-His-Pro-Phe-OH

Scheme 53.1 Biosynthesis of angiotensin peptides.

The ﬁrst ACE inhibitors were peptidomimetics such as captopril (1977) and enalapril, which are analogs of the carboxy terminus of angiotensin I (Scheme 53.2). The mercapto and carboxyl groups in captopril/enalaprilate bind to a Zn2+ cation

in ACE, which coordinates to the carbonyl group of the Phe−His amide bond in angiotensin I to render it more electrophilic.

Bond cleaved by ACE H N Zn2+ N O H H HO2C R N N N HS N N N H H O O CO2H O CO2H O CO2H

Angiotensin I Enalaprilate Captopril t < 5 min, F 0% 1/2 t1/2 11 h, F 41% t1/2 2.2 h, F 65%

Scheme 53.2

Today, in addition to the ACE inhibitors given in Table 53.1, a large number of nonpeptidic angiotensin II antagonists have been developed (the ‘‘sartans,’’ Chapter 72) and several renin inhibitors (‘‘kirens,’’ e.g., enalkiren) are being developed as antihypertensives (Chapter 55) [1].

Reference

1. Webb, R.L., Schiering, N., Sedrani, R., and Maibaum, J. (2010) Direct renin inhibitors as a new therapy for hypertension. J. Med. Chem., 53, 7490–7520.

Table 53.1 ACE inhibitors (prils) and related compounds. V inlkg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ / . ± . t 2 11 h V F 1 7 0 7ENALAPRIL ∗ EtO2C F 41±15% CL/F 4.9±1.5 diacid iv N < Ph N pb 50% Mwt 376.5 Metabolism: hydrolysis to H ur 88±7%∗ PSA 95.9 A˚ 2 enalaprilate (diacid) O CO2H log P 3.25

1/ ± / . ± . t 2 21 9h V F 2 4 1 4 LISINOPRIL NH2 F 25±20% CL/F 4.2±2.2 pb < 5% Mwt 405.5 HO2C ur 94±6% PSA 133 A˚ 2 N Ph N log P 3.47 H O CO2H 337

1/ ± . ∗∗ t 2 14 7h V 1 4 RAMIPRIL F 28–44% CL 1.1±0.4 ∗ester; diacid: 56%; H pb 73%∗ Mwt 416.5 ∗∗ester; diacid: 7.7 l kg−1 EtO2C H N ur 39±17% PSA 95.9 A˚ 2 Ph N H log P 4.37 O CO2H

1/ ∗ t 2 1.5–2.2 h V 0.6 SPIRAPRIL S F 50% CL 0.15 ∗terminal t1/ 30–40 h S 2 EtO C pb – Mwt 466.6 2 ˚ 2 N ur 12% PSA 147 A Ph N log P 5.88 H O CO2H

1/ t 2 7.6–14 h V – IMIDAPRIL ∗ O N F 40% CL – ester EtO2C pb 85%∗ Mwt 405.4 N 2 Ph N ur 9% PSA 116 A˚ H O CO2H log P 2.28

1/ ∗ t 2 6 h (ester) V 0.3 (ester) TRANDOLAPRIL F 40–70% CL ∗diacid: 10–24 h H ∗∗ ∗∗ EtO2C H pb 80% Mwt 430.5 ester; diacid: 65–95% N ur 33% PSA 95.9 A˚ 2 Ph N H log P 4.90 O CO2H

1/ ∗ . ∗ t 2 1.5–2.9 h V 0 22 PERINDOPRIL F 75%∗ CL 1.2–2.3∗∗ester H pb 60%∗ Mwt 368.5 EtO C ∗ 2 H ur 4–12% PSA 95.9 A˚ 2 N N log P 4.10 H O CO2H

1/ t 2 25–30 h V 0.16 PERINDOPRILATE F 17–20% CL – H pb 10–20% Mwt 340.4 HO2C H ur 60–70% PSA 107 A˚ 2 N N log P 2.37 H O CO2H

(continued overleaf ) 338 53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils)

1/ ∗ t 2 0.8 h V 0.56 PENTOPRIL F –CL3.1∗ester; diacid: 3.9 h ∗∗ EtO C pb – Mwt 333.4 ester; diacid: 40% 2 ∗∗ ˚ 2 N ur 21% PSA 83.9 A log P 4.09 O CO2H

1/ ∗ t 2 0.4 h V – DELAPRIL F >55% CL 13.3 ∗ester; diacid: 1.2 h pb – Mwt 452.5 Metabolism to diacid and 2 1/ ur – PSA 95.9 A˚ 5-hydroxyindane diacid (t 2 1.4 h). EtO2C log P 4.48 F: diacid after oral dosing of ester N Ph N H O CO2H

1/ . ± . / . ∗∗ t 2 2 2 0 2h V F 0 9 QUINAPRIL F 49±11% CL/F 26∗∗ ∗ester; diacid: 28±9% ∗∗ . ± . EtO C pb 97% Mwt 438.5 ester; diacid: 2 0 0 6 2 ∗ ˚ 2 N ur 3% PSA 95.9 A Ph N log P 4.79 H O CO2H

1/ OMe t 2 1h V – MOEXIPRIL OMe F 22% CL – Fast hydrolysis to pb 90% Mwt 498.6 moexiprilate in the liver and ur 1% PSA 114 A˚ 2 in tissue by carboxyesterases EtO2C N log P 4.77 (not in the GI tract); F: diacid after Ph N oral administration of ester H O CO2H

1/ ± OMe t 2 6 4h V 2.8 MOEXIPRILATE OMe F 13% CL 3.3 pb 50–70% Mwt 470.5 ur 40% PSA 125 A˚ 2 HO2C N log P 5.16 Ph N H O CO2H

1/ ∗ t 2 1.5 h V – TEMOCAPRIL F 65% CL/F 34∗∗ester; diacid: 7–15 h S ∗∗ S pb – Mwt 476.6 diacid ∗∗ 2 EtO2C ur 57% PSA 149 A˚ Ph N N log P 6.57 H CO2H O 339

1/ ∗ / ∗∗∗ t 2 0.7 h V F 0.12 BENAZEPRIL F 28–37% CL/F 0.3–0.4∗∗∗ ∗ester; diacid: 10–22 h EtO C 2 pb 95–97% Mwt 424.5 ∗∗ester; diacid: 18% Ph N N ur <1%∗∗ PSA 95.9 A˚ 2 ∗∗∗diacid H CO2H O log P 4.54

1/ ± t 2 43 7h V 0.3–0.6 CILAZAPRIL ∗ EtO C F 47–75% CL 1.8–4.1 diacid 2 N pb 24%∗ Mwt 417.5 Ph N N ∗ ˚ 2 H ur 90–100% PSA 99.2 A O log P 2.21 CO2H

1/ t 2 15 h V – CERONAPRIL NH2 F 67% CL – Antihypertensive OH pb – Mwt 440.5 P N ur – PSA 140 A˚ 2 Ph O O log P 1.79 O CO2H

1/ ± ∗ . ± . t 2 11 1h V 0 13 0 03 FOSINOPRIL F 36±7% CL 0.5±0.1 ∗diacid pb >95%∗ Mwt 563.7 ur 43±9%∗ PSA 120 A˚ 2 O O O Ph N –logP 6.47 P O O CO2H

1/ . ± . . ± . t 2 2 2 0 5h V 0 8 0 2 CAPTOPRIL F 38–65% CL 12.0±1.4 ACE inhibitor, HS N pb 30±6% Mwt 217.3 antihypertensive; Metabolism: ur 38±11% PSA 96.4 A˚ 2 oxidative disulﬁde formation, O CO2H log P 0.27 S-methylation

1/ ∗ t 2 5h V –ALACEPRIL Ph F – CL – Prodrug of captopril S N pb – Mwt 406.5 ∗captopril on oral dosing CO H ur – PSA 129 A˚ 2 of alacepril O O N 2 O H log P 0.19

1/ ∗ . ∗∗ SPh t 2 0.9 h V 1 5 ZOFENOPRIL F 65–78% CL 20∗∗ ∗ester; thiol: 4.6±1.0h pb 88%∗∗ Mwt 429.6 ∗∗thiol Ph S N ur <10% PSA 125 A˚ 2 Metabolism: hydrolysis to thiol log P 5.62 F: thiol after oral dosing of ester O O CO2H

(continued overleaf ) 340 53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils)

1/ t 2 14–19 h V – OMAPATRILATE H F 30% CL – Antihypertensive S pb – Mwt 408.5 Metabolism: disulﬁde formation Ph SH ˚ 2 N ur – PSA 151 A with cysteine, S-methylation, log P 1.65 acyl glucuronidation, hydrolysis of NH O CO H exocyclic amide, oxidation to O 2 sulfoxides

t1/ 2.3–6.0 h V 0.33–0.47 N-ACETYLCYSTEINE CO H 2 HS 2 F 6–10% CL 3.5–14 HN O pb 50% Mwt 163.2 ur 30% PSA 105 A˚ 2 log P −0.70

1/ t 2 1.5–3.0 h V – PENICILLAMINE F 40–70% CL 10.7 CO2H HS pb 80% Mwt 149.2 2 NH2 ur 40% PSA 102 A˚ log P 0.85

1/ t 2 19–53 h V – TIOPRONIN H F 63% CL – Antidote for heavy-metal poisoning, N CO H pb – Mwt 163.2 mucolytic, hepatoprotectant HS 2 ur – PSA 105 A˚ 2 Metabolite: mixed O log P −0.67 disulﬁde with cysteine

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; GI, gastrointestinal. All data except calculated values (unless otherwise noted): acid on oral dosing of ester. 341

54 Anilides and Amides of Glycine

N-(2,6-Dimethylphenyl)glycine amide derivatives are important local anesthetics that are less irritating and safer than procaine (Table 54.1). The ﬁrst member of this group, lidocaine, was discovered in the 1940s at the University of Stockholm. The chemist Holger Erdtman, trying to elucidate the structure of the alkaloid gramine, came to prepare isogramine instead. A common practice of organic chemists at that time was to taste newly synthesized products, and while doing so, Erdtman’s tongue was numbed. A project was started to identify an analog of isogramine, suitable as local anesthetic. This research led to the discovery and marketing by Astra of lidocaine in 1948 (Scheme 54.1).

N Synthesis of N open-chain analogs O N N N N H H H Gramine Isogramine Lidocaine (toxic alkaloid) (weak local anesthetic) t1/2 1.8 h, F 35%

Scheme 54.1 The origin of lidocaine.

Although methylanilines, including 2-methyl- and 2,6-dimethylaniline, are suspected carcinogens, and the typical metabolic reactions of glycylanilides include amide hydrolysis, lidocaine and related anilides are relatively safe drugs, even after parenteral administration. Typical metabolic transformations, exempliﬁed by those of lidocaine, are shown in Scheme 54.2.

O O O Metabolism H N N + NH N N N 2 H H H Lidocaine t1/2 1.8 h, F 35% HO + + NH 2 NH2

Scheme 54.2 Metabolism of lidocaine.

Structurally related to lidocaine are the antiarrhythmic mexiletine and the antihypertensives lofexidine and guanfacine (Scheme 54.3). Their improved pharmacokinetics (PK) is mainly due to the absence of the metabolically labile tertiary amine and the replacement of the xylyl group by a dichlorophenyl group.

Cl Cl O O NH2 H N NH2 N N O O N NH2 H Cl N Cl Lidocaine Mexiletine Lofexidine Guanfacine − − t1/2 1.8 h, F 35% t1/2 9 h, F 87% t1/2 11 h, F > 90% t1/2 14 23 h, F 60 100%

Scheme 54.3 Drugs structurally related to lidocaine.

A further class of therapeutically relevant amides of glycine are the DPPIV (dipeptidylpeptidase IV) inhibitors. DPPIV is the enzyme that deactivates GLP- 1 (glucagonlike peptide 1) by cleaving off the N-terminal dipeptide of GLP-1 (H-His-Ala-OH) (Scheme 54.4). GLP-1 is normally released when nutrients reach the intestine and strongly potentiates insulin secretion by acting on receptors at pancreatic β-cells. DPPIV inhibitors enhance the levels of GLP-1 and can, therefore, be used to treat type II diabetes.

Arrow: bonds cleaved by DPPIV

O O O H O H O H CN H2N N R O N HO N N N N H H H2N N R N O N H

N CO2H H Preferred substrate Vildagliptin (a DPPIV inhibitor) GLP-1 − of DPPIV t1/2 2 5 h, F 85%

Scheme 54.4

The ﬁrst DPPIV inhibitors, such as vildagliptin, were mimetics of the N-terminus of preferred substrates of this enzyme (H-Gly-Pro-R, H-His-Ala-R), in which the target amide bond was replaced by a nitrile. DPPIV is a prolyl oligopeptidase, which preferentially cleaves N-terminal dipeptides from peptides with alanine or proline at the penultimate position. Later, high-throughput screening provided peptide- unrelated leads, which led to DPPIV inhibitors such as alogliptin, carmegliptin, and linagliptin. 54 Anilides and Amides of Glycine 343

Table 54.1 Glycylanilides and related compounds. V inlkg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ ± t 2 4 1h V – o-TOLUIDINE F – CL – Metabolite of prilocaine, pb – Mwt 107.2 suspected human carcinogen ˚ 2 NH2 ur – PSA 26.0 A Metabolism: N-oxidation to log P 1.38 hydroxylamine and nitrosotoluene

1/ ± t 2 8 4h V – 2,6-DIMETHYLANILINE F – CL – Metabolite of some local pb – Mwt 121.2 anesthetics, suspected NH 2 ur – PSA 26.0 A˚ 2 human carcinogen log P 1.63

1/ ± . ± . t 2 14 2h V 3 0 0 2 TOCAINIDE F 89±5% CL 2.6±0.5 Antiarrhythmic, racemic; O pb 10±15% Mwt 192.3 (R : t1/ 17±6h;S : t1/ 10±4h) NH 2 2 N 2 ur 38±7% PSA 55.1 A˚ 2 Metabolites: carbamoyl H 1/ log P 0.81 glucuronide (t 2 13 h), 1/ lactoxylidide (t 2 29 h)

1/ . ± . . ± . t 2 1 8 0 4h V 1 1 0 4 LIDOCAINE, LIGNOCAINE F 35±11% CL 9.2±2.4(R= H); TRIMECAINE ± = R pb 70 5% Mwt 234.3 (R CH3; PK identical O ur 2±1% PSA 32.3 A˚ 2 to lidocaine); antiarrhythmic, N log P 2.20 local anesthetic; Metabolism: N H N-deethylation, cyclization to imidazolidone, hydrolysis of amide, aromatic 3- and 4-hydroxylation

1/ t 2 1–2 h V 3–4 PRILOCAINE O H F 20–40% CL 29–34 Local anesthetic N pb 28–40% Mwt 220.3 Metabolism: amide N H ur <5% PSA 41.1 A˚ 2 hydrolysis, log P 2.03 aromatic hydroxylation

1/ t 2 2–3 h V 2 ETIDOCAINE O F – CL 17 Local anesthetic N pb 94% Mwt 276.4 Metabolism: N H ur <1% PSA 32.3 A˚ 2 N-dealkylation log P 3.57

1/ t 2 1–3 h V 1.0–1.3 MEPIVACAINE O F – CL 12.3 Local anesthetic N pb 78% Mwt 246.4 Metabolism: aromatic N 2 H ur 5–10% PSA 32.3 A˚ hydroxylation, log P 1.78 N-demethylation

(continued overleaf ) 344 54 Anilides and Amides of Glycine

1/ ∗ t 2 1.8 h (iv) V 0.6–0.8 ROPIVACAINE F 56±18%∗∗ CL 5–8 ∗4.2 h (epidural), 2.6 h (rectal) O pb 90–94% Mwt 274.4 ∗∗rectal N ur 1% PSA 32.3 A˚ 2 Local anesthetic; does not N H log P 2.80 racemize in vivo; Metabolism: aromatic hydroxylation (CYP1A2), N-dealkylation (CYP3A4)

1/ . ± . . ± . t 2 2 4 1 2h V 0 9 0 4 BUPIVACAINE O F –CL7.1±2.8 Local anesthetic N pb 95±1% Mwt 288.4 Metabolism: N-dealkylation N H ur <4% PSA 32.3 A˚ 2 (CYP3A) log P 3.31

1/ t 2 4–9 h V 1.48 PILSICAINIDE O F – CL 3.8 Antiarrhythmic N pb 30% Mwt 272.4 N H ur 75–86% PSA 32.3 A˚ 2 log P 1.88

1/ ± t 2 25 min V 5 3 ARTICAINE, O S H F – CL 127±54 CARTICAINE N N pb 57–73% Mwt 284.4 Local anesthetic H ˚ 2 MeO ur 1.4% PSA 95.7 A Inactive metabolite: O log P 2.22 articainic acid

1/ . ± . t 2 2 4 0 3h V 0.5–0.7 ARTICAINIC ACID O S H F –CL2.7±0.5 Main metabolite of N N pb 60–90% Mwt 270.4 articaine H ˚ 2 HO ur – PSA 107 A O log P 2.38

t1/ 5.5 h (dog) V 1.2 (dog) AMELTOLIDE O 2 F – CL – Anticonvulsant N pb – Mwt 240.3 Metabolism: NH2 H ur – PSA 55.1 A˚ 2 acetylation NH2 log P 1.90

1/ t 2 2–6 h V 0.5–0.7 NEFIRACETAM O F – CL 1.5–2.2 Nootropic N pb – Mwt 246.3 Metabolism: hydroxylation of N ˚ 2 H O ur 5% PSA 49.4 A pyrrolidone log P 0.64 (mainly at position 5) 54 Anilides and Amides of Glycine 345

1/ t 2 1–2 h V 1.3–2.8 RANOLAZINE MeO F 35–50% CL 10 Antianginal; Metabolism: pb 63% Mwt 427.5 hydroxylation, glucuronidation, O N O ur <5% PSA 74.3 A˚ 2 N-dealkylation, N OH N log P 1.31 O-demethylation, O-dearylation, H amide hydrolysis

1/ F t 2 22 h V 10 LIDOFLAZINE F 35–40% CL – Calcium channel antagonist O N pb – Mwt 491.6 Metabolism: N-dealkylation N ur <5% PSA 35.6 A˚ 2 N H log P 5.42

1/ t 2 3–11 h V 1.2–3.4 RECAINAM O F 73–84% CL 4.5–11.1 Antiarrhythmic N N N pb 14–20% Mwt 263.4 Metabolites: H H H ur 84% PSA 53.2 A˚ 2 desisopropyl, log P 2.78 p-hydroxy

1/ t 2 7–9 h V – FOMINOBEN Cl O F 65% CL – Antiussive N pb – Mwt 401.9 Metabolism: N-debenzoylation N ur – PSA 61.9 A˚ 2 O O NH log P 2.73

t1/ 2h∗ V – ABT-279 O 2 NC H F 11%∗ CL – ∗monkey N N pb – Mwt 395.5 DPPIV inhibitor ˚ 2 N CO2H ur – PSA 110 A log P 0.61 N

1/ t 2 2–3 h V 2.7 SAXAGLIPTIN F 51%∗ CL 14.5∗∗monkey NC O pb <30% Mwt 315.4 DPPIV inhibitor, antidiabetic; N OH ur 12–29% PSA 90.4 A˚ 2 active metabolite: 5-hydroxy − . 1/ NH2 log P 0 14 (t 2 3–7 h) (hydroxylation at C3CH) (continued overleaf ) 346 54 Anilides and Amides of Glycine

1/ t 2 2–5 h V 1 VILDAGLIPTIN O F 85% CL 12 DPPIV inhibitor, antidiabetic NC H N OH pb 9% Mwt 303.4 Metabolism: hydrolysis of N ur 22% PSA 76.4 A˚ 2 nitrile to acid, amide log P −0.14 hydrolysis, glucuronidation, oxidation of pyrrolidine

1/ ∗ t 2 2.2 h V – MELOGLIPTIN O ∗ ∗ NC H F 94% CL 16 monkey N N N N pb – Mwt 320.4 DPPIV inhibitor, ˚ 2 N ur – PSA 86.8 A antidiabetic log P −1.34 F

t1/ 8–14 h V 3 SITAGLIPTIN F 2 F 87% CL – DPPIV inhibitor, F O NH2 pb 38% Mwt 407.3 antidiabetic ur 79% PSA 77.0 A˚ 2 N N N log P 1.30 N F

F3C

55 Peptides, Peptidomimetics, and Related Oligoamides

The use of peptides as drugs seems attractive because of their predictable and safe metabolism and their high potency and selectivity. However, few clinically viable peptides have been identified, and most have to be administered parenterally. A notable exception is the gonadotropin agonists (e.g., buserelin), which are modified decapeptides suitable for nasal dosing [1]. Chemically modified peptides are mainly used as hormone analogs or as protease inhibitors. Reasons for the scant use of peptide-based drugs are mainly their poor pharmacokinetic (PK) properties, in particular, their low oral bioavailability, poor membrane penetration, and quick enzymatic degradation. Moreover, unnatural peptides with a molecular weight above 700–1000 g mol−1 can elicit an immune response. Proteins, though, can have plasma half-lives of several days (e.g., albumin or antibodies). Peptide bonds can be stabilized toward enzymatic cleavage with the aid of unnatural amino acids, such as N-alkylamino acids or aminoisobutyric acid, or by conformational constraints, for example, by cyclization [2]. Alternatively, amino- or carboxypeptidase activity may be blocked by modifying the terminal functional groups of a peptide, if the target allows this. Many natural, peptide-based poisons (e.g., amanitin, a mushroom poison, Scheme 55.1) are mono- or polycyclic peptides with high oral bioavailability.

OH HO O O H H O N O N N HO H H N HO HN H O NH N S O H N O O H N H2N H O O α-Amanitin t (dog) 0.5–1.0 h 1/2 Scheme 55.1

Renal excretion may be delayed and membrane permeability enhanced by lipophilization. Acylation with fatty acids, for instance, increases the afﬁnity of peptides to albumin and keeps them from being excreted renally. This lipophilization can be permanent or transient, that is, the acylated peptide may be a prodrug of the peptide. The absorption of peptides from the small intestine may be enhanced by alkylating the NH groups or replacing them with non-hydrogen- bond-donating groups [3]. The membrane permeability and enzymatic stability of peptides may also be enhanced by glycosylation. Although glycosylated peptides are less lipophilic than the corresponding nonglycosylated peptides, transport through membranes can be brought about by active transport mechanisms or endocytosis. Finally, the PK and other properties of peptides (and proteins) may be improved by conjugation to a polymer, for example, poly(ethylene glycol) (‘‘pegylation’’) [4]. Pegylation delays renal clearance and enzymatic degradation, enhances solubility, and reduces immunogenicity of peptides and proteins.

55.1 Peptidomimetics

Peptides based on proteinogenic amino acids alone are usually not well suited as drugs, because of their poor absorption from the gastrointestinal tract and low metabolic stability. Moreover, the high polar surface area (PSA) of peptides also keeps them from crossing other membranes or the blood–brain barrier (bbb). Unnatural peptides with a molecular weight > 700 g mol−1 may, furthermore, induce an immune response. When the only lead available in a project is a peptide, medicinal chemists often end up spending huge resources on the discovery of a peptidomimetic with acceptable PK properties, often without success. One strategy to improve the PK properties of peptides is to replace peptide bonds by an unnatural substructure, not prone to enzymatic degradation. The simplest way to achieve this is by using N-methylamino acids; all other strategies usually involve multistep, expensive syntheses of structurally complex intermediates. Particularly difficult is the rational design of inhibitors for endopeptidases, which often recognize several amino acid side chains and are highly selective. Four examples of hydroxyethylene peptidomimetics are shown in Scheme 55.2. The development of such drugs is complicated not only by the difficulty of attaining acceptable PK properties but also by the high cost of producing the final drug. 55.2 Thrombin Inhibitors and Related Compounds 349

N NH O OH NH O O H 2 N S N N NH2 H H O O O OH OH

O OMe OMe Remikiren (renin inhibitor) Aliskiren (renin inhibitor) t1/2 9 h, F 1–2% t1/2 34–41 h, F 2–3%

Ph O O H H H O N MeO N N O N N N OMe H H N N O OH O H HO OH N N N

Indinavir (HIV protease inhibitor) Atazanavir (antiviral) t1/2 1.8 h, F 65% t1/2 6.5 h, F 60–68%

Scheme 55.2 Peptidomimetics.

Because it is so difﬁcult to turn a peptide into an orally available small molecule with good PK (see Table 55.1), even weak but structurally less complex hits resulting from a high-throughput screening should always be evaluated carefully. It is usually much easier to improve potency, selectivity, and the pharmacokinetics of a weak, nonpeptidic hit than to convert a potent and selective peptide into a compound with acceptable pharmacokinetics (see, e.g., the development of losartan, Chapter 72). In general, weak hits devoid of problematic functional groups are more promising than potent hits containing such groups (e.g., highly polar, basic, acidic, chemically reactive, or metabolically questionable functional groups).

55.2 Thrombin Inhibitors and Related Compounds

The oldest, but still popular, antithrombotics are warfarin, heparin, and aspirin. With the goal of identifying more selective antithrombotics with fewer side effects, potent thrombin inhibitors with suitable PK are being sought [5]. Unfortunately, the drugs resulting from these endeavors are mainly peptidomimetics, most of them amidines or guanidines of low oral bioavailability (Table 55.2). Blood coagulation is a complex process, involving various different enzymes. In the last step of the coagulation cascade, the protease thrombin cleaves two peptides from (soluble) fibrinogen to generate fibrin, which undergoes oligomerization to form the clot. As most coagulation factors, thrombin cleaves an Arg-X bond in fibrinogen, but not Lys-X or other closely related peptide bonds. Therefore, it has 350 55 Peptides, Peptidomimetics, and Related Oligoamides

been difﬁcult to ﬁnd thrombin inhibitors devoid of an amidine or guanidine group. Most of the drugs known today must be dosed parenterally. One way to improve the oral bioavailability of these highly basic compounds is to lower the basicity of the amidine/guanidine group. This can, for instance, be achieved by alkoxycarbonylation or by using N-hydroxyamidines, which are converted in vivo into the corresponding amidines.

References

1. Conn, P.M. and Crowley, W.F. (1991) Gonadotropin-releasing hormone and its analogs. New Engl. J. Med., 324, 93–103. 2. (a) Malakoutikhah, M., Prades, R., Teixido, M., and Giralt, E. (2010) N-Methyl phenylalanine-rich peptides as highly versatile blood–brain barrier shuttles. J. Med. Chem., 53, 2354–2363; (b) Biron, E. et al.. (2008) Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew. Chem. Int. Ed., 47, 2595–2599; (c) Witt, K.A., Gillespie, T.J., Huber, J.D., Egleton, R.D., and Davis, T.P. (2001) Peptide drug modiﬁcations to enhance bioavailability and blood–brain barrier permeability. Peptides, 22, 2329–2343; (d) Fauch ere, J. and Thurieau, C. (1992) Evaluation of the stability of peptides and pseudopeptides as a tool in peptide drug design. Adv. Drug Res., 23, 127–159. 3. vonGeldern,T.W.et al.. (1996) Azole endothelin antagonists. 3. Using logP as a tool to improve absorbtion. J. Med. Chem., 39, 982–991. 4. Harris, J.M. and Chess, R.B. (2003) Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov., 2, 214–221. 5. (a) Pinto, D.J.P., Smallheer, J.M., Cheney, D.L., Knabb, R.M., and Wexler, R.R. (2010) Factor Xa inhibitors: next-generation antithrombotic agents. J. Med. Chem., 53, 6243–6274; (b) Chackalamannil, S. (2006) Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J. Med. Chem., 49, 5389–5403.

Table 55.1 Peptides and peptidelike compounds. V inlkg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ . ± . t 2 1 8 0 4h V 0.82 INDINAVIR H F 65% CL 18 Antiviral O N Metabolism: pyridine O pb 61% Mwt 613.8 ur 10–12% PSA 118 A˚ 2 N-glucuronidation, N N pyridine N-oxidation, H log P 2.88 HO OH N 3-hydroxylation at indane, 4-hydroxylation of phenylmethyl, N N-depyridomethylation of piperazine

1/ Ph t 2 5–6 h V 1.3 LOPINAVIR O O ∗ ∗ H F Low CL 1.5–1.8 rat: 25% N HN N N pb 98–99% Mwt 628.8 Antiviral H ˚ 2 O OH O ur 2.2% PSA 120 A Active metabolites: 4-oxo, Ph log P 6.26 4-hydroxy 351

1/ Ph t 2 3–5 h V 0.3–0.6 RITONAVIR O O H F 75% (rat) CL – Antiviral N N N N O pb 98–99% Mwt 720.9 Metabolism: H H 2 O OH ur <10% PSA 202 A˚ N-demethylation of urea, S Ph N log P 5.28 carbamate hydrolysis, N S hydroxylation at = (CH3)2CHC( N)S

1/ t 2 4–5 h V 2–7 NELFINAVIR, AG-1343 H F 47–88% CL 6–16 Antiviral (HIV) SPh O N O pb >98% Mwt 567.8 Metabolism: hydroxylation HO ur 1–2% PSA 127 A˚ 2 of tert-butyl, N N H H log P 7.28 4 -hydroxylation to OH catechol, then H 3-O-methylation, oxidation to sulfoxide (minor pathway)

1/ t 2 7–15 h (iv) V 3.6 SAQUINAVIR H Ph O N F 1–9% CL 13 Antiviral (HIV), low N O H pb 97% Mwt 670.8 absorption from GI, high N N N ur 1–3% PSA 167 A˚ 2 ﬁrst-pass effect H H O OH Metabolism: hydroxylation O log P 4.44 H of cyclohexane and NH 2 tert-butyl groups

t1/ 9–11 h V 3.9 TELAPREVIR N 2 H O H O F –CL– Antiviral (hepatitis C) N N N NH N N pb 59–76% Mwt 679.9 Metabolite: 2 O H O O O ur 1% PSA 180 A˚ pyrazinecarboxylic acid log P 3.93

1/ / t 2 7–15 h V F 12 BOCEPREVIR F 30% (dog) CL 41 O O Hepatitis C virus protease H pb 75% Mwt 519.7 inhibitor N N NH2 N N ur 3% PSA 151 A˚ 2 H H O O O log P 2.05

1/ t 2 7–11 h V 5–7 AMPRENAVIR ∗ F 35–90%∗ CL – dog O Ph O O O pb 90% Mwt 505.6 Antiviral (HIV) S < ˚ 2 Metabolism: oxidation of O N N ur 3% PSA 140 A H tetrahydrofuran and OH log P 4.20 NH2 aniline, N-dealkylation, carbamate hydrolysis; prodrug: O-phosphate (fosamprenavir) (continued overleaf ) 352 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ . ± . t 2 15 h V 1 4 0 9 DARUNAVIR F 37% CL 8 Antiviral (HIV) H O Ph O O O pb 95% Mwt 547.7 Metabolism: carbamate O S 2 O N N ur 8% PSA 149 A˚ hydrolysis, isobutyl H H OH log P 3.94 hydroxylation, aniline NH2 hydroxylation, benzylic hydroxylation, glucuronidation

1/ O t 2 10–40 min V 0.7–15 CARFILZOMIB F Low CL 13–285 Proteasome inhibitor, O O N pb 95–99% Mwt 719.9 antineoplastic H H 2 O N N ur – PSA 158 A˚ N N H H log P 6.71 O O O Ph Ph

1/ . ∗ t 2 1.5–3.0 h V 0 8 IDRAPRIL ∗ F 30% CL – dog iv O pb 0% Mwt 258.3 ACE inhibitor, HO N 2 N ur 8% PSA 107 A˚ antihypertensive H log P −1.49 Metabolism: reductive O CO2H cleavage of N-O bond, hydrolysis of amide

1/ ∗ t 2 349–743 h V – BATIMASTAT F Low CL – ∗ip O O H pb 96% Mwt 477.6 Matrix metalloproteinase HO N 2 N N ur – PSA 161 A˚ inhibitor, antineoplastic H H O log P 3.30 S

1/ t 2 8–10 h V – CIPEMASTAT, F 43% CL – TROCADE O N pb 90% Mwt 436.6 Matrix metalloproteinase O ur 9% PSA 110 A˚ 2 inhibitor for treatment of HO N log P 2.06 rheumatoid arthritis H O Metabolism: N glucuronidation

O N 353

1/ t 2 1–4 h V – TOSEDOSTAT F –CL– Orally available O O H pb – Mwt 406.5 antineoplastic, HO N ˚ 2 N O ur – PSA 125 A aminopeptidase inhibitor; H active metabolite: acid OH O log P 2.24 1/ (t 2 6–11 h)

1/ t 2 5–10 h V 3.4 MARIMASTAT F Good CL – Matrix metalloproteinase O O H pb – Mwt 331.4 inhibitor, antineoplastic HO N ˚ 2 N N ur 2–3% PSA 128 A H H OH O log P 1.31

1/ t 2 1–8 h V – MMI-270 N F 44% (rat) CL – Matrix metalloproteinase OMe pb 57–80% Mwt 393.5 inhibitor, antineoplastic O ur – PSA 108.8 A˚ 2 HO N N S log P 1.37 H O O

1/ . ∗∗ t 2 40 h V 2 2 BMS-708163 F C ∗ 3 O O F 42%∗ CL 3.4∗∗ dog H N S ∗∗ 2 N pb – Mwt 520.9 estimate based on O ur – PSA 128 A˚ 2 allometric scaling; Cl log P 3.97 γ-secretase inhibitor (treatment of Alzheimer F N disease) O N

1/ . ∗ t 2 66–93 h V 0 7 ODANACATIB ∗ F 18%∗ CL – monkey F H pb – Mwt 525.6 Cathepsin K inhibitor for NC N NH ur – PSA 107 A˚ 2 treatment of osteoporosis O log P 2.92 Metabolism: F3C CH3-hydroxylation, demethylation of sulfone, addition of glutathione to S nitrile O O

(continued overleaf ) 354 55 Peptides, Peptidomimetics, and Related Oligoamides

t1/ 6.5 h V 1.4 ATAZANAVIR Ph 2 H O H O F 60–68% CL 3.3 Antiviral MeO N N N N N OMe pb 86% Mwt 704.9 Metabolism: H H O OH O ur 6% PSA 171 A˚ 2 N-debenzylation, log P 5.20 carbamate hydrolysis, N hydroxylation, alcohol oxidation to ketone

1/ Br t 2 2.5 h (iv) V 0.3 OLCEGEPANT HO F Low CL 2.6 CGRP antagonist, pb – Mwt 869.7 antimigraine Br ur – PSA 176 A˚ 2 O H O N log P 3.55 N N N H N N O NH N N O 2 H

1/ t 2 5–8 h V – TELCAGEPANT, CF 3 F 35% (dog) CL – MK-0974 O N CGRP antagonist, O F pb 94% Mwt 566.5 ur <5% PSA 97.4 A˚ 2 antimigraine F N N log P 2.26 Metabolism: oxidation to H pyridine-N-oxide N N N H O

1/ OMe t 2 13 h V 0.6 LACOSAMIDE O H F 100% CL – Antiepileptic N pb <15% Mwt 250.3 Metabolism: N H ur 40% PSA 67.4 A˚ 2 O-demethylation O log P 0.90

1/ t 2 6–19 h (iv) V 5–12 BORTEZOMIB F –CL19 Antineoplastic Ph O OH pb 70–85% Mwt 384.2 H Metabolism: substitution N N B ur – PSA 124 A˚ 2 of B(OH) by OH, N OH 2 H log P 2.45 hydroxylation of CH(Me)2, O N benzylic hydroxylation, phenylalaninamide hydrolysis 355

1/ ∗ Ph t 2 1.7–2.3 h V 0.6 FLOVAGATRAN O OH F –CL– ∗iv H N N B pb 90% Mwt 525.4 Thrombin inhibitor O N OH ∗ ur 14% PSA 137 A˚ 2 H O O Ph log P 3.54

OMe

1/ t 2 2.8 h V – TALABOSTAT F –CL– Orally available DPPIV N pb – Mwt 214.1 H2N inhibitor, antidiabetic 2 O B OH ur – PSA 86.8 A˚ HO log P 0.01

t1/ 14–18 h V – DARINAPARSIN S AsCH3 2 O F 58% CL – H Antineoplastic, apoptosis HO C N CO H pb – Mwt 411.3 inducer 2 N 2 H ur – PSA 184 A˚ 2 NH O 2 log P −5.14

1/ t 2 2h V 0.35 NEGAMYCIN OH NH2 O F –CL– Antibacterial H N N CO H pb – Mwt 248.3 2 N 2 H ur – PSA 142 A˚ 2 log P −4.14

1/ t 2 5–8 h V 0.24 LOXIGLUMIDE F 97% CL 1.0 CCK antagonist, Cl gastroprokinetic, racemic O pb 94–98% Mwt 461.4 H ˚ 2 Metabolism: hydroxylation N ur 1% PSA 95.9 A Cl N log P 4.37 and oxidative degradation O of pentyl, OMe O-demethylation, CO2H then oxidation of primary alcohol to CO2H, hydrolysis of both amides

1/ t 2 2–3 h V – SEMAGACESTAT F –CL/F 4.3 Oral γ-secretase inhibitor O O H pb – Mwt 361.4 for treatment of N N 2 N ur 44% PSA 98.7 A˚ Alzheimer disease H Metabolism: hydrolysis of OH O log P 2.23 the amide bond proximal to the benzazepine ring, benzylic hydroxylation of the benzazepine ring (continued overleaf ) 356 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ t 2 5–17 h V 0.9–1.6 BB 83698 . ± . O F –CL37 2 0 Peptide deformylase H O pb 78–82% Mwt 530.7 inhibitor, antibacterial N N ˚ 2 HO N O ur – PSA 112 A log P 3.56 O N O

1/ t 2 2.0–4.2 h V – LBM 415 ∗ ∗ I F 22–100% CL 31 ∗rodents O pb – Mwt 396.4 Peptide deformylase ur – PSA 94.9 A˚ 2 inhibitor, antibacterial N N N HO log P 0.04 O N O O H

1/ ∗ t 2 2.4 h V – CAPROMORELIN ∗ F 65%∗ CL – rat O Growth hormone NH2 pb – Mwt 505.6 ∗ 2 NH Ph ur 2–5% PSA 117 A˚ secretagogue O O log P 4.07 Metabolism (rat): O-debenzylation, aromatic O N N hydroxylation of benzyl N ether, N-demethylation

1/ ∗ t 2 1.1 h V – BMS-317180 ∗ F 12% CL – ∗monkey O NH2 OH pb – Mwt 463.5 Growth hormone NH ur – PSA 162 A˚ 2 secretagogue O H log P 0.93 O N N N NN O

1/ ∗ t 2 4h V – TABIMORELIN F 30–35%∗ CL – ∗dog O pb – Mwt 528.7 Growth hormone O ˚ 2 N ur – PSA 95.7 A secretagogue; CYP3A4 H N N N log P 3.80 inhibitor 2 H O Ph

1/ t 2 9h V 2.7 TALTOBULIN O F –CL4 Tubulin polymerization N CO H pb – Mwt 473.7 inhibitor, antineoplastic Ph N 2 H ur – PSA 98.7 A˚ 2 HN O log P 4.80 357

1/ N t 2 1.6 h V 0.2 ENALKIREN NH F 0% CL – Renin inhibitor, O OH H H pb 94% Mwt 656.9 antihypertensive H N N N ur – PSA 192 A˚ 2 2 N H log P 3.52 O O OH

MeO

1/ N t 2 9h V 1 REMIKIREN NH F 1–2% CL 12.8 Renin inhibitor, O OH H pb 83% Mwt 630.8 antihypertensive N ur – PSA 170 A˚ 2 Metabolism: hydroxylation S N H log P 3.38 O O O OH

t1/ 34–41 h V 2.1 ALISKIREN NH O O 2 2 F 2.6% CL 2.3 (iv) Renin inhibitor, N NH2 pb 47–51% Mwt 551.8 antihypertensive; 91% of H OH ur <1% PSA 146 A˚ 2 dose is excreted log P 2.74 unchanged in feces O OMe OMe

1/ ± t 2 5 2h(iv) V 0.2 BROSTALLICIN H O N H O N O N N O F –CL4 DNA ligand, N N N H O N H NH pb – Mwt 723.6 antineoplastic Br NH ur – PSA 207 A˚ 2 H2N N − . H log P 2 61

t1/ 6h(iv) V 2.0–2.5 DESFERRIOXAMIN, OH O 2 F <2% CL 4–5 DEFEROXAMINE H2N N N pb <10% Mwt 560.7 Chelating agent for iron H O HO ˚ 2 Metabolism: OH N ur 30–35% PSA 206 A H − . transamination, oxidation N N log P 0 61 O to carboxylic acid, O O N-hydroxylation

1/ t 2 1.2 h V – BUSERELIN Pyroglutamic acid-His-Trp-Ser- F 2.5–3.3%∗ CL – ∗intranasal; po (pig): 1–5% -Tyr-(O-tBu)ser-Leu- pb 15% Mwt 1239.4 GnRH agonist, treatment -Arg-Pro-NHEt ur 17% PSA 438 A˚ 2 of hormone-sensitive log P 0.76 cancers

(continued overleaf ) 358 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ t 2 4–5 h (sc) V 0.2–0.6 GOSERELIN Pyroglutamic acid-His-Trp-Ser- F –CL1.9GnRH agonist, treatment -(O-tBu)Ser-Tyr-(O-tBu)ser-Leu- pb 20–28% Mwt 1269.4 of hormone-sensitive -Arg-Pro-NH-NHMe ur 20% (sc) PSA 493 A˚ 2 cancers log P −0.26

1/ t 2 2–3 h V 0.4–0.5 NAFARELIN ∗ Pyroglutamic acid-His-Trp-Ser- F 4–21% CL – ∗intranasal dosing -Tyr-Nal-Leu-Arg-Pro-Gly-NH2 pb 80% Mwt 1322.5 GnRH agonist ur 3%∗ PSA 472 A˚ 2 log P 0.53

1/ t 2 2.9–3.6 h V 0.37–0.53 LEUPRORELIN Pyroglutamic acid-His-Trp-Ser- F <1% CL 2.0–2.2 GnRH analog, treatment -Tyr-leu-Leu-Arg-Pro-NHEt pb 50% Mwt 1209.4 of hormone-sensitive ur – PSA 429 A˚ 2 cancers log P 0.55

1/ Cl t 2 8–12 h (iv) V 0.4–1.2 CETRORELIX F –CL1.3(Cit: citrulline) O O O pb 86% Mwt 1431.0 GnRH antagonist H H HN N Ser-Tyr-Cit-Leu ˚ 2 N N ur 2–4% (sc) PSA 496 A H log P 1.38 O -Arg-Pro-Ala-NH2

1/ . ± . . ± . t 2 5 6 2 0h V 1 3 0 3 CYCLOSPORINE F 27±9% CL 5.3±1.5 Natural H pb 93±2% Mwt 1202.6 immunosuppressant O N N N ur <1% PSA 279 A˚ 2 O O log P 2.79 O N HN O O

HN N O O O HN O H N N N O O 359

1/ t 2 2h V 0.3–0.4 ICATIBANT Bradykinin B antagonist OH F Low CL 4–5 2 pb 44% Mwt 1304.5 for treatment of hereditary N S < ˚ 2 NH ur 10% PSA 544 A angioedema O log P −3.27 Metabolism: peptide bond N O O hydrolysis (Thi-Ser and Arg-OH HN NH Gly-Thi) O O O OH N H-Arg-Arg-Pro

1/ OH t 2 40–50 h V 0.77 ANIDULAFUNGIN HO F 2–7% CL 0.64 OH Antifungal H N pb 84% Mwt 1140.2 N OH ur – PSA 377 A˚ 2 O H N O O log P 4.34 OH O O N HO NH HO HN OH HO O NH O O

1/ OH t 2 11–17 h V 0.21 MICAFUNGIN HO OSO H F Low CL 0.17 Antifungal O OH 3 H > N pb 99% Mwt 1270.3 Metabolized by aryl H2N N OH ur <1% PSA 519 A˚ 2 sulfatase and COMT O H N O O log P −7.49 OH O O N HO NH O HO HN OH HO O NH O N O

1/ OH t 2 27 h (iv) V 0.13 CASPOFUNGIN HO F –CL0.14 OH Antifungal H N pb 96% Mwt 1093.3 H2N N OH ur – PSA 412 A˚ 2 O H N O O log P 3.53 OH O O N HO NH HN H2N HN OH HO O NH

(continued overleaf ) 360 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ OH t 2 2.7–4.6 h V 0.2–0.4 DESMOPRESSIN ∗ F 0.1% CL 0.3–0.7 ∗intranasal : 2–3% O H pb – Mwt 1069.2 Vasopressin agonist, N 2 N ur 47% PSA 486 A˚ antidiuretic H O log P −2.95 S N O H S O O H N-Gly-arg-Pro NH 2 N CONH H 2 O CONH2

1/ OH t 2 1.3 h V 0.46 LANREOTIDE F –CL4.1Somatostatin analog for O H O H pb 80% Mwt 1096.3 treatment of acromegaly N N 2 H N N ur <5% (sc) PSA 406 A˚ and carcinoid syndrome 2 H O NH O S HN log P 4.99 S O O O H N NH H N N NH 2 H 2 O HO

1/ . ± . . ± . Ph Ph t 2 1 5 0 4h V 0 35 0 22 OCTREOTIDE O H O H F 1–3% CL 2.7±1.4 Somatostatin analog for sc N N pb 65% Mwt 1019.2 dosing H2N N H O NH 2 O ur 11–20% PSA 383 A˚ Treatment of carcinoid S HN log P 3.40 syndrome S O O H N NH HO N NH H 2 O HO OH

1/ O t 2 3h(iv) V 1.2 ROMIDEPSIN F –CL7.4Histone deacetylase O N pb 92–94% Mwt 540.7 inhibitor, antineoplastic H O NH ur – PSA 193 A˚ 2 log P 3.60 NH H S N O O S O 361

1/ . ± . . ± . HO NH2 t 2 5 6 1 8h V 0 39 0 06 VANCOMYCIN F Low CL 1.4±0.1 Antibacterial HO OH ± O OH pb 30 10% Mwt 1449.3 2 O ur 79±11% PSA 530 A˚ O log P −1.41 Cl O Cl O O

HO OH O O H O H O N N N N N H H H HN CO2H O O HN O NH2 OH HO OH

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; ACE, angiotensin converting enzyme; CGRP, calcitonin gene related peptide; CCK, cholecystokinin; COMT, catechol-O-methyltransferase; DPPIV, dipeptidylpeptidase IV; GI, gastrointestinal; GnRH, gonadotropin releasing hormone.

Table 55.2 Antithrombotic amino-, amidino-, and guanidino carboxylic acids. V inlkg−1,CLin ml min−1 kg−1, Mwt in g mol−1.

1/ t 2 1.5–3.0 h V 0.3–0.7 TIROFIBAN CO H 2 F Low CL 3.3–4.8 Fibrinogen antagonist, O HN pb 64% Mwt 440.6 antithrombotic for iv O S O ur 38–80% PSA 113 A˚ 2 administration Metabolism: oxidation to N log P 4.14 H 2-piperidinone, O-dealkylation

t1/ 12–20 h V – LOTRAFIBAN HO2C 2 HN H F 2% CL/F 97 Platelet glycoprotein N pb <13% Mwt 428.5 IIb/IIIa blocker, O ur High PSA 102 A˚ 2 antithrombotic N N log P −0.30 O

1/ t 2 2–4 h V 0.3 LAMIFIBAN HO HO2C ∗ F 1% CL 1.9 ∗mouse O pb 6% Mwt 468.5 Antithrombotic for iv ur 90% (iv) PSA 166 A˚ 2 administration N HN log P 0.08 O O

H2N NH

(continued overleaf ) 362 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ ∗ t 2 9–12 h V – SIBRAFIBAN EtO2C F 36%∗ CL 5.2∗ ∗acid/amidine on oral O pb – Mwt 420.5 dosing of ur 57%∗ PSA 144 A˚ 2 ester/hydroxyamidine; N HN log P 1.04 oral antithrombotic O OH O HN

1/ ∗ . ∗∗ t 2 3–5 h V 0 22 XIMELAGATRAN CO Et ∗ ∗∗ ∗ O O 2 F 20% CL 145±15 amidine/acid ∗ NH pb <15% Mwt 473.6 (melagatran) on oral OH N N ∗∗ 2 H ur 83% PSA 144 A˚ dosing of ximelagatran N log P 2.08 ∗∗melagatran on iv dosing Withdrawn in 2006 NH2 because of hepatotoxicity

1/ ∗ t 2 11–13 h V – LEFRADAFIBAN O ∗ ∗ F 24% CL 6.3 ∗amidine/acid (fradaﬁban) O O pb Low Mwt 439.5 on oral dosing of HN ∗ ur 17% PSA 127 A˚ 2 lefradaﬁban HN log P 0.40 O NH MeO2C

1/ ∗ t 2 10–18 h V – ORBOFIBAN NH ∗ ∗ N F 9% CL – acid on oral dosing of O pb – Mwt 361.4 ester O HN 2 H2N ur – PSA 138 A˚ Antithrombotic log P −0.43 NH EtO2C

1/ ∗ t 2 5d V – ROXIFIBAN ∗ F 21%∗ CL – acid on oral dosing of CO Me pb – Mwt 447.5 ester N O 2 O ur – PSA 165 A˚ 2 Platelet GPIIb/IIIa NH HN log P 1.60 antagonist, antithrombotic O O H2N Metabolism: ester hydrolysis, 2- and NH 3-hydroxylation of butyl, 4- and 5-hydroxylation of isoxazoline 363

1/ ∗ O t 2 4–6 h V – XEMILOFIBAN H F 13%∗ CL 0.08 (iv) ∗ N acid on oral dosing of NH pb – Mwt 358.4 ester ∗ 2 H2N O ur 29% PSA 134 A˚ Antithrombotic log P 0.46 NH CO2Et

1/ ∗ . ∗ O O t 2 12–14 h V 0.9–1 1 DABIGATRAN ∗ N F 6.5% CL – ETEXILATE ∗ . ∗ ∗ O O N N O pb 35% Mwt 471 5 acid/amidine N ∗ ˚ 2∗ H ur 77% PSA 145 A (dabigatran) on oral HN N log P −0.19∗ dosing of prodrug NH

1/ ∗ t 2 2–3 h V 0.65 OTAMIXABAN O ∗ N F Low CL – iv pb – Mwt 446.5 Factor Xa inhibitor ur 13–32%∗ PSA 127 A˚ 2 O log P 0.58 HN

H2N CO2Me NH

1/ ∗ t 2 0.4–0.8 h V 0.2 ARGATROBAN ∗ F Low CL 5 iv O CO H H 2 pb 54% Mwt 508.6 Thrombin inhibitor, N S N ur 16%∗ PSA 186 A˚ 2 antithrombotic; CYP3A4 NH O O log P 2.06 substrate NH Metabolism: oxidation to quinoline and H N N 2 H hydroxylation; reason for low F: too basic, poor absorption due to charges

1/ t 2 1.9 h (iv) V 0.36 NAPSAGATRAN O F –CL6.4Thrombin inhibitor S O O CO2H pb – Mwt 558.7 HN ur – PSA 194 A˚ 2 N H log P 0.27 H2N N N NH O

(continued overleaf ) 364 55 Peptides, Peptidomimetics, and Related Oligoamides

1/ H t 2 1h V 0.26 INOGATRAN ∗ ∗ N CO2H F 2% CL 6.1 monkey pb 20–28% Mwt 438.6 Little metabolism in O N ˚ 2 H ur – PSA 161 A humans H2N N N log P 0.98 H NH O

t1/ 0.5 h V – EFEGATRAN H 2 F <6% CL 6 Thrombin inhibitor H N N CO2H N pb – Mwt 416.5 O ur – PSA 140 A˚ 2 O NH log P −0.44 H N N 2 H

56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

In recent years, several enzyme inhibitors have been developed with the aid of a thorough understanding of the synthetic accessibility of molecules and molecular modeling. Typical target enzymes included HIV protease and the various tyrosine kinases involved in the growth of tumors [1]. Arenes and heteroarenes are easy to synthesize, nonchiral, and easy to functionalize with various substituents. Therefore, these drugs often end up being short oligoarenes or -heteroarenes linked by one- to three-atom spacers (diarylureas, diarylethers, diarylamines, diarylethylenes, benzanilides, etc.) (Table 56.1). Because such compounds do not readily dissolve in water [2], solubility-enhancing, basic substituents are often included, such as 1-piperazinyl or other aminoalkyl substituents. Amines may also prolong the plasma half-life of these oligoarenes by increasing their volume of distribution (Chapter 23).

References

1. Liao, J.J.-L. (2007) Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem., 50, 409–424. 2. Lovering, F., Bikker, J., and Humblet, C. (2009) Escape from ﬂatland: increasing saturation as an approach to improving clinical success. J. Med. Chem., 52, 6752–6756.

Table 56.1 Oligoarylamines and related compounds. V in l kg−1,CLinmlmin−1 kg−1, and Mwt in g mol−1.

1/ PhS t 2 14–20 h V – NAVITOCLAX, ABT-263 ∗ F 20% CL/F 0.8–1.9 ∗monkey N NH pb – Mwt 974.6 Bcl-2 inhibitor, apoptosis O O 2 O S ur – PSA 170 A˚ inducer, oncolytic F3C log P 9.70 Cl O S O N H O N N

(continued overleaf )

1/ ∗ t 2 11–16 h V – FOSTAMATINIB OMe F –CL–Orally available prodrug of O MeO OMe NaO pb 98% Mwt 580.5 R406; spleen tyrosine kinase P ONa ur – PSA 197 A˚ 2 inhibitor; O ∗ H log P 1.48 R406 on oral dosing of HN N N N N O prodrug; further metabolism: N N-glucuronidation, F O 4-O-demethylation, then O-sulfation, O-glucuronidation

t1/ 16–20 h V 73 VX-702 F F H2N O 2 F F –CL1MAP kinase inhibitor, N N pb – Mwt 404.3 treatment of rheumatoid ur 66% PSA 102 A˚ 2 arthritis and acute coronary H2N F log P 0.76 syndrome O

1/ MeO O t 2 1–3 h V – PICOTAMIDE F >46% CL – Antithrombotic, platelet N pb – Mwt 376.4 H aggregation inhibitor ur 30% PSA 93.2 A˚ 2 N log P 1.88 O N H N

1/ ± O t 2 52 22 h V – ENTINOSTAT, MS-275 F 85% CL – Histone deacetylase inhibitor, N pb – Mwt 376.4 antineoplastic H 2 NH2 ur – PSA 106 A˚ log P 1.46 HN O N

1/ t 2 5–8 h V – MOTESANIB, AMG 706 F 43% (dog) CL 10–19 Antiangiogenic, antineoplastic pb – Mwt 373.5 Metabolism: O ur – PSA 78.9 A˚ 2 N-carbamoyl-glucuronidation, N N log P 3.56 N-glucuronidation, indoline H H CH2 hydroxylation, then N N H oxidation to lactam, N N-oxidation of 4-pyridyl, N-depicolinylation

1/ . ∗∗ Cl t 2 10–14 d V 0 77 VISMODEGIB O F 13–53%∗ CL – ∗animals ∗∗ N pb >94% Mwt 421.3 calculated H 2 N ur – PSA 84.5 A˚ SMO antagonist, hedgehog S Cl log P 2.98 signaling inhibitor, oncolytic O O 367

1/ ± ∗ O t 2 34 14 h V 4 TARIQUIDAR ∗ MeO N F –CL4.4±3.0 iv N H pb – Mwt 646.7 P-glycoprotein inhibitor, MeO NH ur – PSA 111 A˚ 2 adjunct antineoplastic O OMe log P 6.38 OMe N

1/ Cl t 2 19 h V – BETRIXABAN, PRT 054021 O F 47% CL – Factor Xa inhibitor, MeO antithrombotic N N pb – Mwt 451.9 H ur – PSA 107 A˚ 2 NH log P 2.93

O N

1/ t 2 14–18 h V – DAREXABAN, YM-150 N F –CL–Factor Xa inhibitor, N OH pb – Mwt 474.6 antithrombotic H 2 N ur – PSA 94.1 A˚ log P 4.08 O N H O

OMe

t1/ 8–11 h V 4.5 EDOXABAN N 2 N N F 45% CL – Factor Xa inhibitor, H pb 40–59% Mwt 548.1 antithrombotic N S O ur 36–45% PSA 165 A˚ 2 Metabolism: hydrolysis of oxal O log P 1.24 pyridylamide, N H H N-demethylation of piperidine, N N O hydrolysis of dimethylamide O Cl

t1/ 7–11 h V 17 MGCD-0 103 O 2 F 42% (rat) CL 24 Histone deacetylase inhibitor, N pb – Mwt 396.4 apoptosis inducer, oncolytic H ur – PSA 106 A˚ 2 NH2 log P 1.88 HN N N

(continued overleaf ) 368 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

1/ t 2 18–22 h V 5–6 IMATINIB Antineoplastic, substrate and N F 98% CL 2.3–3.2 H pb 95% Mwt 493.6 inhibitor of CYP3A4 N N ur 5% PSA 86.3 A˚ 2 Metabolism: N-demethylation 1/ O log P 2.48 (N-desmethyl: t 2 40 h), N-oxidation of pyridine, HN N N hydroxylation of CH3C, oxidation of piperazine to N lactam, conversion of CCH2N to CCO2H

1/ ∗∗ t 2 13 h V 17 MASITINIB N ∗ H F 60%∗ CL 14∗∗ cat N N ∗∗ pb 93% Mwt 498.6 dog O ur – PSA 102 A˚ 2 Antineoplastic log P 2.89 Metabolism: N-dealkylation, HN N hydroxylation, amide hydrolysis S N

1/ ∗ N t 2 18–26 h V 10–16 DANUSERTIB ∗ N F – CL 5.5–7.7 iv H pb – Mwt 474.6 Antineoplastic N N ur – PSA 93.8 A˚ 2 Metabolite: N-oxide of HN log P 2.34 piperazine O

O OMe

t1/ 1h V – BAFETINIB CF3 2 F 32% CL – Kinase inhibitor, N H pb – Mwt 576.6 antineoplastic N ur – PSA 99.2 A˚ 2 O N log P 3.03

HN N

N N

1/ CF3 t 2 17 h V 2.7 NILOTINIB F 30% CL 7.5 Kinase inhibitor, O pb 98% Mwt 529.5 antineoplastic 2 N N ur <4% PSA 97.6 A˚ Metabolism: hydroxylation of H N log P 5.15 methyl in imidazole, then oxidation to carboxylic acid HN N N

N 369

1/ OH O t 2 9h V 6–7 RALTEGRAVIR O F 32% CL 8.3 Antiviral (HIV), does not cross N H pb 83% Mwt 444.4 bbb NN O F ur 9% PSA 150 A˚ 2 Metabolism: glucuronidation log P −0.68 N O H N N

1/ O t 2 6–7 h V – TBC-3711 H F >80% CL – Endothelin ETA antagonist for S N pb – Mwt 447.5 treatment of pulmonary O ur – PSA 118.4 A˚ 2 hypertension S O O log P 2.34 HN

O N

1/ t 2 5–6 h V 39 DASATINIB OH ∗ N F 34%∗ CL 34∗∗ dog ∗∗ N N pb 96% Mwt 488.0 monkey ur 0.1% PSA 135 A˚ 2 Kinase inhibitor, N Cl log P 0.14 antineoplastic Metabolism: hydroxylation by HN S HN CYP3A4, N-oxidation, N N-dealkylation, oxidation to O carboxylic acid

t1/ 31 h V 0.3 PAZOPANIB H O O 2 N N S F 14–39% CL 1.4 Tyrosine kinase inhibitor, NH 2 pb >99% Mwt 437.5 antiangiogenic N ur <4% PSA 127 A˚ 2 log P 1.98 N N N

1/ N t 2 42 h V 26 CRIZOTINIB N F 32–66% CL/F 15–26 Kinase inhibitor, N pb 91% Mwt 450.3 antineoplastic NH ur 2.3% PSA 78.0 A˚ 2 Metabolism: piperidine H2N oxidation to lactam, O log P 3.55 O-dealkylation Cl Cl

(continued overleaf ) 370 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

1/ H t 2 2.2–2.4 h V – REVAPRAZAN, YH1885 N N F 40% (rat) CL – Proton pump inhibitor, antiulcerative N pb – Mwt 362.4 F ur 0% PSA 41.1 A˚ 2 N log P 5.29

1/ ∗ . ∗ t 2 5.3 h V 3 4 RAZAXABAN N ∗ ∗ ∗ F N F 84% CL 18 dog pb – Mwt 528.5 Factor Xa inhibitor, ur – PSA 120 A˚ 2 anticoagulant HN N log P 1.87 Metabolism (rat, dog): − O NH reductive N O bond cleavage, F3C 2 then glucuronidation of N N N phenol, N-dealkylation O

1/ Cl t 2 30–120 h V 1.6 VEMURAFENIB F –CL0.3B-raf enzyme inhibitor, pb >99% Mwt 489.9 antineoplastic ur <1% PSA 96.0 A˚ 2 F O H log P 3.94 N S N O O F N H

1/ / F t 2 5–12 h V F 0.4 RIOCIGUAT F –CL/F 0.4 Guanylate cyclase stimulator N NH2 pb – Mwt 422.4 for treatment of pulmonary N N ur – PSA 138 A˚ 2 CO2Me hypertension N − . N N log P 0 31

NH2

1/ O t 2 1 h (rat) V – OCINAPLON N F –CL–Anxiolytic pb – Mwt 301.3 Metabolite: 4-pyridyl-N-oxide N ur – PSA 73.0 A˚ 2 N N log P 2.16

N 371

1/ O t 2 1.5–2.0 h V –INDIPLON S F –CL–Hypnotic pb – Mwt 376.4 Metabolism: N-deacetylation, N < ˚ 2 N-demethylation N N ur 1% PSA 95.8 A log P 0.83 N

1/ NC t 2 1.1 h V 1.3 ZALEPLON F 31±10% CL 16 Hypnotic N Metabolites: 5-oxo N N pb 60% Mwt 305.3 < ˚ 2 (4-pyrimidone), N-desethyl N ur 1% PSA 74.3 A log P 1.40 O

1/ ± . ∗ HN N t 2 17 5h V 1 2 LINIFANIB, ABT-869 ∗ F 10%∗ CL 0.7±0.3 monkey NH2 pb 99% Mwt 375.4 VEGF inhibitor, 2 HN ur 4% PSA 95.8 A˚ antiangiogenic, antineoplastic F log P 4.34 Metabolism: oxidation of CH3 N O to CO H H 2

1/ NO2 t 2 3h V –AMOCARZINE F <40% CL – Anthelmintic pb – Mwt 371.5 Metabolism: N-oxidation N ur 1.5% PSA 108 A˚ 2 HN log P 2.32 N

N S H

1/ O t 2 25–48 h V 0.7 SORAFENIB N F 40–50% CL 0.7 (rat) Tyrosine kinase inhibitor, N CF H 3 pb 99.5% Mwt 464.8 antineoplastic Cl ur 0% PSA 92.4 A˚ 2 Active metabolite: O log P 5.16 pyridine-N-oxide; further HN metabolism: glucuronidation N O H

1/ N t 2 1–5 h V – PRINOMASTAT HO F High CL – Matrix metalloproteinase NH pb 69–90% Mwt 423.5 inhibitor, antineoplastic O < 2 O ur 2% PSA 143 A˚ Metabolite: pyridine-N-oxide S 1/ log P 4.29 (t 2 6–10 h) N S O O

(continued overleaf ) 372 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

1/ O t 2 5–10 h V 16–87 OLAPARIB ∗ ∗ F O F 100% CL 0.3–2.4 rat, dog N pb – Mwt 434.5 PARP inhibitor, antineoplastic N NH ˚ 2 N ur – PSA 82.1 A O log P 0.00

N t1/ 18–27 h V – OMECAMTIV MECARBIL OMe 2 F 100% CL – Cardiac myosin activator for O N HN pb – Mwt 401.4 treatment of heart failure N ur – PSA 86.8 A˚ 2 N O H log P 1.36 F

1/ t 2 2–5 h V 1.9 AXITINIB H N F 58% CL/F 6 Antineoplastic N pb 99.6% Mwt 386.5 Metabolism: glucuronidation O S ur <1% PSA 96.0 A˚ 2 log P 4.15

HN N

1/ ∗ t 2 14 h V – BRIVANIB ALANINATE N ∗ ∗brivanib on oral dosing of N F 55–97% CL – O prodrug N pb – Mwt 370.4 F ur 0% PSA 84.7 A˚ 2 Prodrug of brivanib with O O log P 2.48 improved solubility Kinase inhibitor, O NH 2 N antineoplastic H Metabolism: O-dealkylation, sulfation,

1/ . ± . N t 2 4 6 1 1h V 3.3 VATALANIB F 18–57% CL – Antiangiogenic tyrosine pb – Mwt 346.8 kinase inhibitor ˚ 2 Metabolism: pyridine N ur 0.4% PSA 50.7 A N-oxidation, aromatic N log P 3.80 hydroxylation, hydroxylation HN of CH2

1/ / O t 2 4–14 h V F 0.9–4.6 SELUMETINIB, AZD 6244 O F –CL/F 8–31 MEK inhibitor N N OH H pb 97% Mwt 457.7 Metabolism: N-demethylation 2 N NH ur – PSA 88.4 A˚ F Cl log P 5.55

Br 373

1/ O N t 2 12–35 h V – CEDIRANIB F >40% (rat) CL – VEGF tyrosine kinase N N inhibitor, antineoplastic, MeO F pb – Mwt 450.5 ˚ 2 crosses bbb O ur – PSA 72.5 A log P 4.80 Metabolism: N N-glucuronidation H (at pyrrolidine)

1/ MeO N t 2 34–65 h V 23 GEFITINIB F 59% CL 7–12 Kinase inhibitor, N O pb 91% Mwt 446.9 antineoplastic < ˚ 2 Metabolism (CYP3A4): HN ur 0.5% PSA 68.7 A log P 4.11 demethylation, oxidative deﬂuorination, N-dealkylation N F of tertiary amine O Cl

1/ / O N t 2 34 h V F 19–73 AFATINIB, BIBW 2992 O F –CL/F 11 Kinase inhibitor, N HN pb – Mwt 485.9 antineoplastic ur – PSA 88.6 A˚ 2 HN O log P 3.59

F N Cl

1/ O N t 2 10–17 h V 63–95 NERATINIB F –CL/F 47–105 Tyrosine kinase inhibitor, HN CN pb – Mwt 557.0 oncolytic ur – PSA 112 A˚ 2 HN N O log P 5.46

O N Cl

1/ N t 2 120 h V 115 VANDETANIB O N F Good CL 3.4 Kinase inhibitor, pb 92–96% Mwt 475.4 antineoplastic N < ˚ 2 Metabolism: N-oxidation, MeO ur 5% PSA 59.5 A N-demethylation, HN log P 5.51 glucuronidation

F Br

(continued overleaf ) 374 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

1/ O N t 2 17–39 h V 18.6 BOSUTINIB F 18% CL/F 38–64 Tyrosine kinase inhibitor, N MeO CN pb – Mwt 530.5 antineoplastic HN OMe ur 1% PSA 82.9 A˚ 2 N log P 5.48 Cl Cl

1/ / > O N t 2 40 h V F 30 SARACATINIB F –CL/F 22 Antineoplastic N N O pb – Mwt 542.0 ˚ 2 N O HN O ur – PSA 90.4 A log P 2.74 O Cl

1/ O N t 2 4h V 3–10 CANERTINIB F 33% CL 68 Irreversible tyrosine kinase N N O pb – Mwt 485.9 inhibitor, antineoplastic ˚ 2 HN Cl ur – PSA 88.6 A O O log P 3.65

1/ O N t 2 36 h V 3.6 ERLOTINIB F 60–100% CL 1.1 Kinase inhibitor, N pb 95% Mwt 393.4 antineoplastic MeO O < ˚ 2 Metabolism: O-demethylation, HN ur 2% PSA 74.7 A log P 2.39 aromatic hydroxylation, OMe oxidation of ethynylbenzene to arylacetic acid

1/ N t 2 24 h V 34 LAPATINIB F 50–100% CL – Kinase inhibitor, N F pb 99% Mwt 581.1 antineoplastic ur <2% PSA 115 A˚ 2 O HN log P 5.14

HN O O O S Cl

1/ t 2 29–54 h V – ISPINESIB F – CL 0.5–6.3 Kinesin spindle protein NH O 2 pb 81–96% Mwt 517.1 inhibitor, antineoplastic ur – PSA 79.0 A˚ 2 N log P 5.20 N Cl N O 375

1/ MeO t 2 39–60 h (iv) V 23–52 OBATOCLAX NH F – CL 32–72 Bcl-2 inhibitor, antineoplastic N N pb – Mwt 317.4 H ur – PSA 53.2 A˚ 2 log P 3.52

1/ ∗ O t 2 40–54 h V –ENZASTAURIN ∗ N F – CL 11.2 parent + metabolites HN pb 95% Mwt 515.6 Kinase inhibitor ˚ 2 O ur – PSA 62.3 A Metabolism: N-depicolylation, log P 4.43 N-demethylation N

N N

1/ H t 2 9h V – MKC-1, RO 31–7453 ∗ O N O F 12% CL – ∗monkey pb – Mwt 400.4 Antimitotic, antineoplastic ur <1% PSA 92.0 A˚ 2 Metabolism: N-demethylation NO2 log P 3.73 N N

1/ / ∗ H t 2 5h V F 15 RUBOXISTAURIN O N O F –CL/F 33 Protein kinase C inhibitor for pb – Mwt 468.6 treatment of diabetic ur <1% PSA 58.6 A˚ 2 retinopathy log P 3.92 Metabolites: N-desmethyl 1/ N N (t 2 24 h), 6-hydroxyindole

O N

1/ OH t 2 20–25 h V 17–23 EDOTECARIN F – CL 20–24 Antineoplastic OH HN pb – Mwt 608.6 ur 1–4% PSA 241 A˚ 2 O N O log P 0.75

HO N N OH H OH O HO OH OH

(continued overleaf ) 376 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

1/ t 2 6h V 0.8 CONIVAPTAN O F 34–55% CL 3–7 Vasopressin antagonist, due to O N pb 99% Mwt 498.6 CYP-inhibition the N ur 1% (iv) PSA 78.1 A˚ 2 development of an oral N log P 4.40 formulation was discontinued H N H and an iv formulation was chosen

1/ Cl O t 2 7–10 h V – LIXIVAPTAN F –CL–Vasopressin V2 antagonist O N N pb – Mwt 473.9 Metabolism: oxidation of ˚ 2 N ur – PSA 49.4 A pyrrole to lactam H log P 7.23

1/ O t 2 8–12 h V 3 TOLVAPTAN F 56% CL – Vasopressin antagonist for O N pb 98% Mwt 448.9 treatment of hyponatremia < ˚ 2 N ur 1% PSA 69.6 A Metabolism: hydroxylation H OH log P 4.33

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; CYP, cytochrome P; MAP, mitogen-activated protein; MEK, mitogen-activated protein kinase kinase; PARP, poly(ADP-ribose)polymerase; VEGF, vascular endothelial growth factor. 377

57 Imidazoles

Imidazole is a weak organic base (pKa 7.0) and an important structural element of various drugs. Histamine, biosynthesized by decarboxylation of the amino acid histidine, is the natural agonist of four receptors, and selective agonists and antagonists have been developed for each of them (Scheme 57.1). Histamine H1 antagonists (the classic antihistaminics, Chapter 46), used as antipruritics, do not usually contain an imidazole substructure, but an aliphatic amine instead. Many H2 antagonists, however, contain an imidazole as the basic pharmacophore. These drugs suppress the production of gastric acid and can be used for the treatment of esophageal reﬂux or gastric ulcers. H3 antagonists (imidazole derivatives or amines) are being considered as appetite suppressants and for the treatment of attention deﬁcit disorders. Potential indications for H4 antagonists (amines) include asthma and allergic rhinitis, that is, the same as for H1 antagonists [1].

N CO2H N NH2 N O N NH2 N H H Histidine Histamine Diphenhydramine H1 antagonist t1/2 9 h, F 61%

N S O H H HN N N N N O S N Cl N N N CN N N H N N N Cimetidine N H2 antagonist t1/2 2 h, F 84% Selective H3 antagonist Selective H4 antagonist

Scheme 57.1 Histamine receptor agonists and antagonists [1,2].

Further imidazole-containing drugs are the α2-adrenergic agonists (e.g., dexmedetomidine) and the muscarinic acetylcholine agonist pilocarpine. One group of serotonin 5-HT3 antagonists, the ‘‘setrons,’’ also contain imidazole as the pharmacophore. These drugs are mainly used as antiemetics for patients undergoing chemotherapy (Table 57.1). The trichomonacidal properties of 2-nitroimidazole (azomycin) were discovered in 1955 and led to the development of numerous nitroimidazoles as antiprotozoals. Metronidazole, for instance, is active against a wide variety of anaerobic bacteria and anaerobic protozoal parasites. Nitroimidazoles are less toxic to aerobic than to anaerobic organisms. In vivo, these compounds are reduced by ferredoxin to hydroxylamines and aminoimidazoles, which can damage DNA and interfere with the multienzyme complex pyruvate dehydrogenase, which is critical for the production of acetyl-CoA under anaerobic conditions [3]. Lipophilic imidazoles and 1,2,4-triazoles can inhibit the fungal sterol 14-α- demethylase and, thereby, impair the biosynthesis of ergosterol. These compounds are used to suppress the growth of fungi for the treatment of fungal infections. Benzimidazoles such as thiabendazole, discovered in 1961, are highly active against gastrointestinal nematodes and are used as anthelmintics for humans and in veterinary medicine. Benzimidazoles bind strongly and selectively to parasite β-tubulin and, thereby, inhibit microtubule polymerization in nematodes. Their low oral bioavailability is an advantage because the target organ of these drugs is the gastrointestinal tract. Imidazoles form strong hydrogen bonds, have a large polar surface area, and do not readily cross the blood–brain barrier (bbb). Typical metabolic transformations include N-methylation and N-glucuronidation. Sterically unencumbered, lipophilic imidazoles (and pyridines) may coordinate strongly to metals (e.g., iron in cytochrome P (CYP) enzymes) and act as CYP inhibitors. Cimetidine, for instance, inhibits both CYP2D6 and CYP2E1.

References

1. Smits, R.A. et al. (2010) Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists. J. Med. Chem., 53, 2390–2400. 2. Zaragoza, F., Stephensen, H., Peschke, B., and Rimvall, K. (2005) 2-(4-Alkylpiperazin-1-yl)quinolines as a new class of imidazole-free histamine H3 receptor antagonists. J. Med. Chem., 48, 306–311. 3. (a) Kim, P., Zhang, L., Manjunatha, U.H., Singh, R., Patel, S., Jiricek, J., Keller, T.H., Boshoff, H.I., Barry, C.E., and Dowd, C.S. (2009) Structure–activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles. J. Med. Chem., 52, 1317–1328; (b) Kim, P. et al. (2009) Structure–activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure–activity relationships. J. Med. Chem., 52, 1329–1344; (c) Singh, S., Bharti, N., and Mohapatra, P.P. (2009) Chemistry and biology of synthetic and naturally occurring antiamoebic agents. Chem. Rev., 109, 1900–1947. 379

Table 57.1 Imidazoles and related compounds (see also Table 58.1 (triazoles)). V inlkg−1,CL in ml min−1 kg−1, Mwt in g mol−1.

1/ t 2 15–40 h V 0.6–1.0 FOMEPIZOLE F 100% CL – Alcohol dehydrogenase pb Low Mwt 82.1 inhibitor, antidote to methanol, N ur 1–4% PSA 28.7 A˚ 2 and ethylene glycol poisoning N Metabolites: H log P 1.10 4-(hydroxymethyl)pyrazole, 4-carboxypyrazole, N-glucuronides

t1/ 2–3 h V –IMIDAZOLE N 2 F 100% CL – N pb 5–15% Mwt 68.1 H ur – PSA 28.7 A˚ 2 log P −0.10

1/ t 2 3–6 h V 0.6–0.9 METHIMAZOLE, N F 95% CL 1.4–3.7 THIAMAZOLE HS pb – Mwt 114.2 Antihyperthyroid N ur 7% PSA 47.4 A˚ 2 Metabolite: log P −0.34 3-methyl-2-thiohydantoin 1/ (t 2 9h)

1/ t 2 3min V –HISTAMINE N NH2 F –CL–Natural neurotransmitter pb – Mwt 111.2 Metabolism: N-methylation of N ˚ 2 H ur 2–3% PSA 54.7 A imidazole, oxidation to log P −0.70 imidazolylacetic acid

1/ α t 2 3min V –(R)- -METHYLHISTAMINE N NH2 F –CL–Synthetic histamine H3 agonist pb – Mwt 125.2 N H ur – PSA 54.7 A˚ 2 log P −0.35

1/ t 2 2–5 h V 1.3–1.6 DEXMEDETOMIDINE F 12–20% CL 8–11 α2-receptor agonist, sedative, N pb 94% Mwt 200.3 analgesic, CYP2D6 inhibitor ur 0% PSA 28.7 A˚ 2 Metabolism: N H log P 2.79 N-glucuronidation, hydroxylation, oxidation of aromatic CH3 to CO2H

1/ O t 2 10–17 h V 1 MUZOLIMINE Cl F –CL–Diuretic N pb 65% Mwt 272.1 Metabolism: hydrolysis of N 2 Cl ur 5% PSA 58.7 A˚ amide, then decarboxylation H2N log P 2.10

(continued overleaf ) 380 57 Imidazoles

1/ t 2 1.7–2.0 h V 3.0–3.5 ATIPAMEZOLE F 2% CL 18–25 α2 Adrenoceptor antagonist, pb – Mwt 212.3 antidote to α2 N ur – PSA 28.7 A˚ 2 adrenoceptor-induced sedation N log P 2.40 H

1/ H t 2 9–19 h V – MIFENTIDINE N N F – CL 10–12 Histamine H2 antagonist, pb – Mwt 228.3 antiulcerative N ur 13% PSA 53.1 A˚ 2 Metabolism: hydrolysis to log P 1.98 formamide and aniline, N H oxidation to urea

1/ t 2 0.8–1.4 h V 2.9 PILOCARPINE F 100% CL – Antiglaucoma agent, miotic, N pb 0% Mwt 208.3 diaphoretic (stimulates O ˚ 2 N O ur 16% PSA 44.1 A sweating and salivation) log P −0.24 Metabolism: lactone hydrolysis

1/ t 2 4–6 h V 2–5 ETOMIDATE EtO2C F Low CL 12–25 Hypnotic N pb 77% Mwt 244.3 Metabolism: hydrolysis of ester, ur 2% PSA 44.1 A˚ 2 N-dealkylation N log P 3.05

1/ . ± . t 2 1–2 h V 0 7 0 4 OZAGREL ± N F –CL106 Inhibitor of thromboxane pb – Mwt 228.3 synthase, antithrombotic N 2 CO2H ur 42±16% PSA 55.1 A˚ log P 0.53

1/ . ± . . ± . t 2 3 0 0 3h V 1 9 0 4 IMIDAFENACIN O F 58% CL 7.6±1.6 Muscarinic antagonist pb 88% Mwt 319.4 Metabolism: NH 2 ur 8% PSA 56.0 A˚ 2 N-glucuronidation, N log P 2.42 dihydroxylation and oxidative N degradation of imidazole

1/ / Cl t 2 2–3 h V F 7–11 TIPIFARNIB, R115777 Cl F Yes CL – Farnesyltransferase inhibitor, pb 99% Mwt 489.4 antineoplastic ur – PSA 64.2 A˚ 2 NH2 log P 4.01 N

N N O 381

1/ t 2 1.5–1.7 h V 1.1 ALOSETRON F 47–60% CL 8.7 Treatment of irritable bowel pb 82% Mwt 294.4 syndrome ur 6% PSA 53.9 A˚ 2 Metabolism: aromatic O log P 0.88 6-hydroxylation (ortho to indole N N N) and 7-hydroxylation, then O-sulfation and N N H O-glucuronidation, N-demethylation, hydroxylation of CMe, hydroxylation of imidazole; withdrawn in 2000 for causing ischemic colitis and constipation

1/ . ± . . ± . O t 2 3 5 1 2h V 1 9 0 5 ONDANSETRON F 62±15% CL 5.9±2.6 Antiemetic, 5-HT3 antagonist N pb 73±2% Mwt 293.4 Metabolism: aromatic 7- and ˚ 2 N N ur 5% PSA 39.8 A 8-hydroxylation log P 1.56

1/ O t 2 1.6–1.9 h V – CILANSETRON F 87% (rat) CL – 5-HT3 antagonist for treatment N pb – Mwt 319.4 of irritable bowel syndrome ˚ 2 N N ur – PSA 39.8 A Metabolism: benzylic log P 2.65 hydroxylation

1/ . ± . O t 2 5 8 1 2h V 2 RAMOSETRON F – CL 4.5–5.0 ∗iv N pb 89–91% Mwt 279.3 5-HT3 antagonist, antiemetic ∗ ˚ 2 N N ur 16–22% PSA 50.7 A Metabolism: N-demethylation, H log P 1.99 hydroxylation

1/ t 2 6.4 h (iv) V 3.2 PLINABULIN H F –CL8 Tubulin polymerization N O pb – Mwt 336.4 inhibitor, vascular disrupting HN N ur – PSA 86.9 A˚ 2 agent, oncolytic O N H log P 2.66

1/ . ± . . ± . t 2 2 0 0 3h V 1 0 0 2 CIMETIDINE ± . ± . H H F 84 13% CL 8 3 2 0 Histamine H2 antagonist, N N N S pb 19% Mwt 252.3 antiulcerative ± ˚ 2 N ur 62 20% PSA 114 A Metabolism: S-oxidation to N CN − . H log P 0 07 sulfoxide, hydroxylation of CCH3, hydrolysis to guanylurea (continued overleaf ) 382 57 Imidazoles

t1/ 1.2–1.6 h V 2 ETINTIDINE H H 2 N N F –CL15Histamine H2 antagonist, N S pb – Mwt 276.4 antiulcerative N ˚ 2 N CN ur 35–40% PSA 114 A Metabolism: N-glucuronidation H log P 0.28

1/ H H t 2 2–3 h V 0.7 OXMETIDINE N N O N S F 53–91% CL 3.2 Histamine H2 antagonist, N pb – Mwt 399.5 antiulcerative N 2 H ur 3–5% PSA 126 A˚ Metabolism: glucuronidation log P 2.21

O O

O t1/ 35–40 h V/F 30 TBR-652 H O 2 N F Good CL 15 Chemokine 5 (CCR 5) O pb – Mwt 697.0 antagonist, antiviral (HIV) N S ur – PSA 85.7 A˚ 2 N O N log P 7.57

1/ t 2 5h(iv) V 1.5 DACARBAZINE O F –CL2.6Methylating reagent, pb 5% Mwt 182.2 antineoplastic N NH 2 ur 9–30% PSA 99.7 A˚ 2 Metabolism: N-demethylation, N N N N log P 0.03 reductive cleavage of N=N H double bond

1/ / O t 2 1.8 h V F 0.6 TEMOZOLOMIDE F 96% CL 4.5±1.3 Antineoplastic, crosses bbb N NH2 pb 15% Mwt 194.2 Metabolism: hydrolysis of ± ˚ 2 N ur 6 3% PSA 106 A amide and urea, then N log P −1.27 formation of diazomethane and O N N 4-aminoimidazole-5-carboxylate

1/ t 2 12–14 h V 0.6 TINIDAZOLE F 95% CL 0.6 Antiprotozoal

O2N O O pb 12–20% Mwt 247.3 Metabolism: hydroxylation to S ˚ 2 N ur 20–25% PSA 106 A 2-(hydroxymethyl), N-oxidation log P −0.29 of imidazole, hydroxylation and N nitro group migration (to 2-methyl-4-nitro-5-hydroxy) 383

1/ . ± . . ± . t 2 8 5 2 9h V 0 74 0 10 METRONIDAZOLE ± . ± . O2N F 99 8% CL 1 3 0 3 Antiprotozoal, antibacterial, OH pb 11±3% Mwt 171.2 N crosses bbb ur 10±2% PSA 83.9 A˚ 2 Metabolism: hydroxylation of N − . log P 0 14 CH3, oxidation of CH2OH to CO2H, imidazole N-oxidation

1/ t 2 14–20 h V 0.8 SECNIDAZOLE O N 2 F 99±11% CL 0.4 Antiprotozoal OH N pb 15% Mwt 185.2 Metabolism: hydroxylation, ˚ 2 glucuronidation N ur 22% PSA 83.9 A log P 0.22

1/ t 2 11–14 h V 0.7–1.0 ORNIDAZOLE O2N > OH F 97% CL 0.8 Antiprotozoal N pb 11–13% Mwt 219.6 Metabolism: hydroxylation, ur 4% PSA 83.9 A˚ 2 hydrolysis of CH Cl N Cl 2 log P 0.60

1/ ± t 2 11 1h V 0.6 MISONIDAZOLE O2N OH F 91% CL 0.6 Radiosensitizer N N pb Low Mwt 201.2 Metabolism: O-demethylation, ˚ 2 OMe ur 10–20% PSA 93.1 A glucuronidation, reduction of log P −0.41 NO2 to NH2

1/ ∗ HO t 2 4.2–4.6 h V – DORANIDAZOLE ∗ O2N F –CL– iv OH N O pb – Mwt 247.2 Antineoplastic (radiosensitzer) N ur 79%∗ PSA 129 A˚ 2 Metabolism: glucuronidation, OH log P −1.41 carbonation

t1/ 5.6 h (iv) V 4–6 PIMONIDAZOLE, Ro 03-8799 O2N 2 OH F – CL 8–15 Metabolism: oxidation N N pb – Mwt 254.3 to piperidine N-oxide N ur – PSA 87.1 A˚ 2 log P 0.97

t1/ 2–5 h V 3 NIMORAZOLE O 2 O2N F –CL0.8Antiprotozoal, hypoxic N N pb – Mwt 226.2 radiosensitizer ur – PSA 76.1 A˚ 2 N log P −0.15

1/ t 2 1–6 h V 0.5–0.9 ETANIDAZOLE O2N H F – CL 1.2–2.5 Antineoplastic (radiosensitzer); N pb – Mwt 214.2 Metabolism: reduction N OH N ur – PSA 113 A˚ 2 O log P −1.37 (continued overleaf ) 384 57 Imidazoles

1/ . ± . ∗ . ± . t 2 3 5 0 6h V 0 75 0 12 SR-4554 CF ∗ O2N H 3 F –CL3.2±0.9 iv N N OH pb – Mwt 282.2 Hypoxia probe N ± ∗ ˚ 2 O ur 87 9% PSA 108 A log P 0.29

1/ ± ∗ t 2 12 3h V 0.56 EF5 CF ∗ O2N H 3 F –CL– iv N F N pb – Mwt 302.2 Hypoxia probe N F ∗ ˚ 2 O ur 70% PSA 87.8 A log P 1.35

1/ t 2 11–14 h V 0.6 BENZNIDAZOLE O2N H F 100% CL – Antiprotozoal N N pb 44% Mwt 260.3 Reduction of NO2 leads to N ur 5% PSA 92.7 A˚ 2 reactive electrophile O log P 0.91

1/ t 2 0.8 h V – AZANIDAZOLE N F –CL–Antiprotozoal N pb – Mwt 246.2 N NH2 O N ur <0.5% PSA 111 A˚ 2 2 N log P 0.67

1/ . ∗ t 2 13 min V 3 3 FEXINIDAZOLE ∗ ∗ SMe F 10–14% CL 273±121 ∗dog pb 95% Mwt 279.3 Antiprotozoal N O ur – PSA 98.2 A˚ 2 Metabolism: oxidation to O N 2 N log P 2.13 sulfoxide and sulfone; crosses bbb

t1/ 16–20 h V – PA-824 N O 2 O N F 40% CL – Antibacterial 2 N O pb 95% Mwt 359.3 ur – PSA 86.4 A˚ 2 OCF3 log P 2.70 385

t1/ 3–9 h V 5±2 PLECONARIL N O 2 F 70% CL 5.7 Antiviral O pb >99% Mwt 381.4 2 N ur <1% PSA 74.2 A˚ CF3 log P 5.77 N O

1/ t 2 Short V – ALBENDAZOLE O F 5% CL – Anthelmintic (veterinary); S MeO N pb 70% Mwt 265.3 active metabolite: sulfoxide (see HN ur 0% PSA 92.3 A˚ 2 below); poor oral bioavailability N H log P 3.00 due to low solubility in water and high ﬁrst-pass metabolism

t1/ 8–12 h V – ALBENDAZOLE SULFOXIDE O O 2 F –CL–Main active metabolite of MeO N S HN pb 70% Mwt 281.3 albendazole and netobimin 2 N ur – PSA 103 A˚ Metabolism: oxidation to H log P 0.68 sulfone

t1/ 3–6 h V 1–2 MEBENDAZOLE O O 2 F 22% CL 3.7 Anthelmintic; poor solubility MeO N HN pb 90–95% Mwt 295.3 Metabolism: carbamate < 2 N ur 2% PSA 84.1 A˚ hydrolysis, reduction of ketone H log P 2.83 to alcohol

t1/ 6–8 h V – TRICLABENDAZOLE Cl 2 F –CL–Anthelmintic N O Cl pb – Mwt 359.7 Prodrug of sulfoxide; all values MeS ur – PSA 63.2 A˚ 2 for sulfoxide on oral N Cl H log P 5.39 administration of triclabendazole

1/ t 2 9–14 h V 5.6 RILUZOLE S OCF3 F 30–100% CL 11.3 Neuroprotective H2N pb 97% Mwt 234.2 Metabolism: N-hydroxylation, N ur 0.4–2.0% PSA 76.4 A˚ 2 then O- and N-glucuronidation log P 2.92

1/ . ± . t 2 4 0 1 5h V – ETHOXZOLAMIDE O F 65% CL – Carbonic anhydrase inhibitor, H2N S S pb >95% Mwt 258.3 diuretic, antiglaucoma agent O 2 O N ur 40% PSA 119 A˚ log P 2.14

(continued overleaf ) 386 57 Imidazoles

1/ . ∗ t 2 1–2 h V 2 8 THIABENDAZOLE ∗ ∗ S N F Low CL 27 anephric patient pb – Mwt 201.3 Anthelmintic N N < ˚ 2 H ur 1% PSA 69.8 A Metabolism: aromatic log P 2.47 5-hydroxylation

1/ t 2 4–5 h V – VELIPARIB O NH ∗ 2 F 56–92% CL/F 7 ∗animals pb – Mwt 244.3 N Poly(ADP-ribose)polymerase ur 70% PSA 83.8 A˚ 2 inhibitor, antineoplastic N N log P 0.30 Metabolism: oxidation to H H lactam, hydrolysis of amide

58 Triazoles

Lipophilic imidazoles and 1,2,4-triazoles are important antifungal drugs (Table 58.1). Azole antifungals inhibit the fungal sterol 14-α-demethylase, thereby blocking the biosynthesis of ergosterol from lanosterol. This leads to the accumulation of methylsterols in cell membranes and thus to the impairment of membrane-bound enzyme systems, which keeps fungi from growing. Triazoles usually have longer half-lives and a lower effect on human sterol biosynthesis than imidazoles, and most antifungals under development are, therefore, triazoles. One of the ﬁrst antifungal azoles launched was clotrimazole (1973). This highly insoluble compound is mainly used topically, but for related lipophilic azoles (e.g., miconazole), a parenteral formulation has been developed. Azoles with higher oral bioavailability became available later. Improved oral bioavailability was attained by lowering their lipophilicity and enhancing their metabolic stability, for example, by conversion to tertiary alcohols. Quick renal excretion was avoided by adjusting the lipophilicity to a value that still provided for a high degree of tubular reabsorption. In other words, high oral bioavailability and long half-lives were attained by careful adjustment of the log P to reduce the afﬁnity to CYP enzymes and improve the solubility in water to a degree that does not cause quick renal excretion. Lipophilic triazoles can also be rendered more soluble by transient N-alkylation to cationic triazolium prodrugs. One example of this strategy is isavuconazonium (Scheme 58.1), an oral prodrug of isavuconazole.

F OH F F N OH N N F N N O in vivo N N NC O N S NC N O S N O H Isavuconazonium N Isavuconazole t ½ short, log P 0.28 log P 3.92

Scheme 58.1 Metabolism of isavuconazonium.

Table 58.1 Triazoles and related compounds. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ t 2 15–40 h V 0.6–1.0 FOMEPIZOLE F 100% CL – Alcohol dehydrogenase pb Low Mwt 82.1 inhibitor, antidote to methanol N ur 1–4% PSA 28.7 A˚ 2 and ethylene glycol poisoning N Metabolites: H log P 1.10 4-(hydroxymethyl)pyrazole, 4-carboxypyrazole, N-glucuronides

1/ ∗ Cl Cl t 2 11 h V – ENILCONAZOLE ∗ F 1.4% CL – ∗cow pb – Mwt 297.2 ∗∗rat N ∗∗ N ur 0–10% PSA 27.1 A˚ 2 Antifungal O log P 3.56

1/ Cl Cl t 2 20–25 h V 20 MICONAZOLE F 25–30% CL – Topical antifungal N pb 88% Mwt 416.1 Metabolism: N- and N ur <1% PSA 27.1 A˚ 2 O O-dealkylation Cl log P 4.97

1/ Cl Cl t 2 5 h (rat) V – SERTACONAZOLE F 48% (rat) CL – Topical antifungal pb >99% Mwt 437.8 N S N ur 0% PSA 55.3 A˚ 2 O Cl log P 5.77

1/ ± t 2 3–5 h V 5 2 CLOTRIMAZOLE F Poor CL – ∗dog iv; antifungal pb 90% Mwt 344.8 Metabolism: N-dealkylation (to ur <1%∗ PSA 17.8 A˚ 2 yield imidazole, N N log P 4.92 chlorotritylalcohol, and Cl (2-chlorophenyl)(4- hydroxyphenyl)-phenylmethane

1/ ∗ F t 2 60–120 h V 7 ISAVUCONAZOLE ∗ OH F 100% CL 0.5–0.7 Antifungal ∗ ∗ F N N pb 98% Mwt 437.5 drug on oral administration of ur <1% PSA 111 A˚ 2 the prodrug isavuconazolium N N log P 3.92 (see text) NC S 58 Triazoles 389

1/ F F t 2 103–240 h V 11 RAVUCONAZOLE ∗ ∗ OH F 48–74% CL – animals N N pb 98% Mwt 437.5 Antifungal ur – PSA 111 A˚ 2 N N log P 3.89 NC S

t1/ 4.6 h (iv)∗ V 2.3∗ CS-758 F F F 2 ∗ . ∗ ∗ OH F 100% CL 7 7 monkey NC N N pb – Mwt 542.6 Antifungal O ur – PSA 118 A˚ 2 S N O log P 3.70

1/ . ∗∗ F F t 2 30–56 h V 2 4 ALBACONAZOLE ∗ . ∗∗ ∗ ∗∗ OH F 100% CL 0 16 dog, rat N pb – Mwt 431.8 Antifungal O N ur 0% PSA 78.7 A˚ 2 Metabolism: hydroxylation, N N log P 3.00 then glucuronidation and sulfation Cl N

1/ F F t 2 6h V 2.0–4.6 VORICONAZOLE OH F 96% CL 8.3 Antifungal N N pb 58% Mwt 349.3 Metabolism: N-oxidation of ur <1% PSA 71.8 A˚ 2 pyrimidine, hydroxylation of N N log P 0.93 methyl N F

1/ F F t 2 49 h V 0.62 GENACONAZOLE OH F 100% CL 0.19 Antifungal pb – Mwt 331.3 N N Metabolism: negligible ur 76% PSA 93.5 A˚ 2 S N log P 0.97 O O

1/ ± F F t 2 32 5h V 0.60 FLUCONAZOLE > . ± . OH F 90% CL 0 27 0 07 Antifungal pb 11±1% Mwt 306.3 N N Metabolism: glucuronidation, ur 75±9% PSA 81.7 A˚ 2 N-oxidation N N N log P 0.45 N

(continued overleaf ) 390 58 Triazoles

1/ F F t 2 2.1 h (iv) V 0.15 FOSFLUCONAZOLE PO(OH) F –CL1.3Prodrug of ﬂuconazole for O 2 N pb 96% Mwt 386.3 parenteral administration N ur <1% (iv) PSA 128 A˚ 2 − N N N log P 1.23 N

1/ CN t 2 2.9–3.4 h V – FINROZOLE F –CL–Aromatase inhibitor, pb – Mwt 322.3 antineoplastic ur – PSA 69.8 A˚ 2 Metabolism: glucuronidation log P 2.41 N N OH F N

1/ CN t 2 42–82 h V 1.9–2.2 LETROZOLE F 100% CL 0.3–1.0 Antineoplastic pb 59% Mwt 285.3 Metabolism: N-dealkylation to ur 4–6% PSA 78.3 A˚ 2 benzhydrol and triazole, then log P 0.43 glucuronidation N N

NC N

1/ t 2 9h V –FADROZOLE F –CL10Aromatase inhibitor, oral N pb – Mwt 223.3 antineoplastic < ˚ 2 N ur 5% PSA 41.6 A Metabolism: benzylic NC log P 1.48 hydroxylation

1/ t 2 41 h V 1.4 ANASTROZOLE NC N N F 84–100% CL 0.4 Aromatase inhibitor, pb 40% Mwt 293.4 antineoplastic N ur 10% PSA 78.3 A˚ 2 Metabolism: N-dealkylation, log P 0.97 hydroxylation, glucuronidation NC

1/ F t 2 8–12 h V 0.8–1.2 RUFINAMIDE F 60–85% CL – Antiepileptic N N pb 34% Mwt 238.2 N Metabolite: carboxylic acid ur <2% PSA 73.8 A˚ 2 F log P 1.00 NH O 2 58 Triazoles 391

1/ t 2 1.1–2.1 h V – RAMBAZOLE, R-115866 F –CL–Retinoic acid metabolism N pb – Mwt 377.5 blocking agent N N ur – PSA 78.9 A˚ 2 Metabolism: hydroxylation of S N N log P 5.16 3-pentyl, aromatic H benzothiazole hydroxylation (para to N)

1/ t 2 7h V – TPA-023 N F 36% (rat) CL/F 3.8 GABA agonist, anxiolytic N pb 90% Mwt 395.4 Metabolism: hydroxylation of N < 2 N O N ur 1% PSA 78.1 A˚ tert-butyl, N-deethylation, N log P 3.01 N-glucuronidation F N

1/ . ± . / . ± . O t 2 3 3 1 0h V F 2 4 1 6 KETOCONAZOLE F –CL/F 8.4±4.1 Antifungal pb 99% Mwt 531.4 Metabolism: N-deacetylation, N O ur <1% PSA 69.1 A˚ 2 oxidative degradation of N O log P 4.04 piperazine, O-dealkylation, N Cl O aromatic hydroxylation N

1/ ± / ± O t 2 21 6h V F 14 5 ITRACONAZOLE F 55% CL/F 23±10 Antifungal, CYP3A4 inhibitor N O pb 99.8% Mwt 705.6 Metabolism: hydroxylation of < ˚ 2 N O ur 0.1% PSA 101 A CH2Me N N Cl log P 5.00 N N N N O Cl

1/ O t 2 20–66 h V 27 POSACONAZOLE ∗ F 11–27% CL – ∗dog N pb >98% Mwt 700.8 Antifungal N O < ˚ 2 N ur 0.2% PSA 107 A Metabolism: glucuronidation N F log P 2.25 N N N N O HO F

(continued overleaf ) 392 58 Triazoles

1/ O t 2 56–81 h V – PRAMICONAZOLE, R-126638 F –CL–Antifungal N O O pb – Mwt 659.7 N ur – PSA 88.4 A˚ 2 N N F log P 4.19 N N

N O F

59 Pyridines, Pyrimidines, and Related Compounds

Pyridines (pKa 5) are common substructures of drugs (Table 59.1) and natural products (vitamins and alkaloids) and can serve as bioisostere of carbonyl groups or of other basic heterocycles, such as imidazoles. Thus, nicotine is an acetylcholine agonist, the pyridine ring acting as an ester analog, and the vasodilator betahistine is a histamine agonist (Scheme 59.1).

H O N N N H O N N H N NH N 2 Nicotine Acetylcholine Betahistine Histamine t1/2 2 h, F 30% t1/2 3–4 h, F 100% t1/2 3 min

Scheme 59.1 Pyridines as ester and imidazole mimetics. Despite their basicity and nucleophilicity, pyridines have also been used as bioisosteres of phenyl groups. Pyridines are more water soluble than the corresponding benzenes and may lead to fewer toxic metabolites. Thus, aminopyridines can be useful bioisosteres of potentially toxic anilines. In the examples shown in Scheme 59.2, a benzene ring was replaced by pyridine without severely modifying target selectivity.

Br Cl N N O O N N N N N N S S Bromazine Carbinoxamine Promazine Prothipendyl t 8 h (iv), F 17% t 2–3 h t1/2 3 h, F 65% t1/2 15 h 1/2 1/2 H H N N N

N N

Cyproheptadine Azatadine Desloratadine t1/2 1–4 h t1/2 9–12 h t1/2 18 h, F high

Scheme 59.2 PK-comparison (pharmacokinetics) pyridyl versus phenyl.

CO2H CO2H N N NH N NH N N N

F3C F3C Mianserin Mirtazapine Flufenamic acid Niflumic acid t1/2 14 h, F 20% t1/2 13–40 h, F 49% t1/2 9 h t1/2 2 h H N O H O H O N N O N N NH2 H Br N Cl N F Flupirtine t1/2 9 h, F 90% N H N O

Bromazepam Nordazepam O N NH2 t1/2 15 h, F 60% t1/2 73 h, F 99% H F Retigabine t1/2 7–12 h, F 60%

Scheme 59.2 (Continued).

However, not all heterocyclic amines are toxicologically safe. The compounds shown in Scheme 59.3 are formed when meat is heated (e.g., on frying) by the reaction of creatine or creatinine with amino acids and carbohydrates (Maillard reaction). All these compounds are carcinogenic for rodents, and the probable cause for the increased risk of colorectal cancer in people who frequently eat meat.

NH2 N N N NH2 NH2 N N N N N H H

NH2 NH2 N N N N N N NH2 N N N N

Scheme 59.3 Carcinogenic polycyclic heteroarenes.

One further potential problem of pyridines is their ability to coordinate to iron, which can lead to CYP (cytochrome P) inhibition. This will be important for highly basic and 2,6-unsubstituted pyridines but can be avoided with electron-withdrawing substitutents and by steric shielding of the nitrogen atom. In the example shown in Scheme 59.4 [1], the initial leads were strong inhibitors of CYP1A2. By increasing 59 Pyridines, Pyrimidines, and Related Compounds 395

H H N N H N N OMe N N SMe O O N N CF3 N O CF3 O N CF N 3 Potent inhibitor of CYP1A2 Weak inhibitor of CYP1A2 No inhibition of CYP1A2 µ µ (IC50 20 nM) (7% inhibition at 1 M) (IC50 > 100 M)

Scheme 59.4 Pyridines as CYP inhibitors. the steric shielding of the pyridyl nitrogen atoms, the afﬁnity for CYP enzymes could be effectively suppressed. Typical metabolic transformations of pyridines include N-oxidation, N- methylation, and C-hydroxylation (Scheme 59.5). Interestingly, N-methylpyridinium salts, such as trigonelline or the metabolites of bioactive pyridines, do not react as electrophilic methylating agents and show little toxicity.

in vivo + N N N O Pyridine t1/2 < 24 h, F 67%

NH2 in vivo NH2 NH2 + N N N SO H OH O 3 4-Aminopyridine t1/2 3.6 h, F 95%

O O O N in vivo N N H H ++H N N N Cotinine O t1/2 12–16 h, F > 84% OH (metabolite of nicotine) O O N N H H + H N N

Scheme 59.5 Metabolism of pyridines.

The rate of pyridine metabolism varies strongly and depends on the precise substitution pattern and the overall physicochemical properties of the drug. Examples of long-lived pyridines are shown in Scheme 59.6. 396 59 Pyridines, Pyrimidines, and Related Compounds

N H Cl N NH O O O N S N O O H F N N N H Cl HN N N F O OH O Roflumilast N Desmethylimatinib Piroxicam t1/2 12–20 h, F 69–92% t 40 h 1/2 t1/2 48 h, F high (metabolite of imatinib)

O CF3 O O Cl N O N O N CN H N H N N F C H H 3 Sorafenib Taranabant t1/2 34 d Cl t1/2 25–48 h, F 40–50%

Scheme 59.6 Pyridines as drugs.

59.1 Proton Pump Inhibitors

In 1967, the ‘‘gastrin’’ project was initiated at Astra in Hassle¨ (Sweden) with the aim of developing a drug for suppression of gastric acid secretion. As starting hypothesis, it was assumed that the local anesthetic lidocaine was capable of inhibiting the acid-stimulating hormone gastrin. After ﬁve years of development work, however, it turned out that such a gastrin inhibitor had no effect in vivo on acid secretion (thus the importance of early proof of concept in animals). Looking for a new lead, researchers at Astra chose CMN 131 (Scheme 59.7), a weak inhibitor of acid secretion developed at Searle. The compound was too toxic because of the thiocarbonyl group, but served well as lead.

O H H S S N S N N N

N NH2 N N

H 124/26 CMN 131 Timoprazole (H 83/69) too toxic (thyroid gland) too weak, too toxic too toxic (thyroid gland) OMe

O O H H S N S N N N N N CO2Me OMe

Picoprazole (H 149/94) Omeprazole induces vasculitis t1/2 0.7 h, F 53%

Scheme 59.7 Development of omeprazole. References 397

This time, animal models were used to test new compounds, and within a few years, the benzimidazoles H 124/26 and timoprazole were found. Both were more potent than CMN 131, but showed thyroid-gland-related toxicity. The less toxic picoprazole was discovered in 1976, but disappointingly, this compound induced vasculitis in some dogs. Finally, in 1979, omeprazole was prepared and shown to be a potent and safe inhibitor of gastric acid production. Its new mechanism of action was the inhibition of gastric H+,K+-ATPase, and omeprazole turned out to be superior to the previously used histamine H2 antagonists. Racemic omeprazole was launched 1988 in Sweden, while the enantiomerically pure S-isomer, which is about four times as potent as the R-isomer, was approved in 2000. The S-isomer is prepared by enantioselective oxidation of the corresponding thioether with the aid of a chiral titanium complex [2]. Typical metabolic transformation of omeprazole-type proton pump inhibitors includes oxidation to a sulfone, reduction to a thioether, and O-demethylation (Table 59.2).

References

1. Bromidge, S.M. et al. (2000) Biarylcarbamoylindolines are novel and selective 5-HT2C receptor inverse agonists: identiﬁcation of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-triﬂuoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent. J. Med. Chem., 43, 1123–1134. 2. Carlsson, E., Lindberg, P., and von Unge, S. (May 2002) Two of a kind. Chem. Br., 42–45.

Table 59.1 Pyridines, pyrimidines, and related azines. V inlkg−1,CLinmlmin−1 kg−1, Mwt in gmol−1.

1/ < t 2 24 h V – PYRIDINE F 67% CL – Metabolism: N-methylation, pb – Mwt 79.1 N-oxidation 2 N ur – PSA 12.9 A˚ log P 0.84

1/ t 2 2–3 h V – N-METHYLPYRIDINIUM F –CL–Contained in coffee, metabolite of pb – Mwt 94.1 pyridine N ur 60–70% PSA 3.89 A˚ 2 log P −4.39

1/ t 2 12 h V 1–3 PARAQUAT N F <30% CL – Herbicide pb – Mwt 186.3 ur 90% PSA 7.77 A˚ 2 N log P −5.82

(continued overleaf ) 398 59 Pyridines, Pyrimidines, and Related Compounds

1/ . ± . . ± . t 2 3 6 0 9h V 2 6 0 9 4-AMINOPYRIDINE, NH2 F 95% CL 10.2±2.3 FAMPRIDINE, DALFAMPRIDINE pb Negligible Mwt 94.1 Potassium channel blocker, ur >90% PSA 38.9 A˚ 2 treatment of multiple sclerosis N log P 0.34 Metabolites: 3-hydroxy and sulfate thereof

t1/ 0.5–2 h V – 3,4-DIAMINOPYRIDINE, NH 2 2 F 30% CL 30 AMIFAMPRIDINE NH 2 pb – Mwt 109.1 Potassium channel blocker, ur – PSA 64.9 A˚ 2 treatment of multiple sclerosis N log P −0.34

1/ N t 2 5–14 h V –ALTRETAMINE F Low∗ CL – ∗variable N N pb 94% Mwt 210.3 Antineoplastic (ovarian cancer) ur <1% PSA 48.4 A˚ 2 Metabolism: hydroxylation at methyl N N N log P 2.53 groups followed by demethylation

1/ O t 2 1–3 h V 1.6–1.7 DEFERIPRONE OH F – CL 8.3–9.4 Chelating agent pb <10% Mwt 139.2 Metabolism: glucuronidation ur >80% PSA 40.5 A˚ 2 N log P −0.65

1/ t 2 20–45 min V 0.3 NICOTINIC ACID, NIACIN, CO2H F 60–76% CL – VITAMIN B3 pb <20% Mwt 123.1 Metabolites: N-nicotinoyl glycine, ˚ 2 N ur 12% PSA 50.2 A nicotinamide, NAD log P 0.22

1/ t 2 4–6 h V – TRIGONELLINE CO2H F –CL–Contained in coffee pb – Mwt 138.1 N ur 40–60% PSA 41.2 A˚ 2 log P −3.98

t1/ 12–14 h V 0.3–0.4 ACIPIMOX N CO H 2 2 F 100% CL – Antihyperlipoproteinemic pb 0% Mwt 154.12 Metabolism: N-deoxygenation N ur >90% PSA 75.7 A˚ 2 O log P −1.00

1/ ± t 2 2–3 h V 3 2 PRALIDOXIME F 20–30% CL 9±4 Cholinesterase reactivator (antidote against cholinesterase inhibitor N pb Low Mwt 137.2 N OH ur 80±13% PSA 36.5 A˚ 2 poisoning), crosses bbb log P −2.85 Metabolite: 1-methyl-2-cyanopyridinium 399

1/ t 2 1.3 h (im) V 0.2 OBIDOXIME F Low CL – Cholinesterase reactivator (antidote N N pb Low Mwt 288.3 against cholinesterase inhibitor OH N O N OH ur 90% PSA 82.2 A˚ 2 poisoning) log P −5.72

1/ . ± . . ± . t 2 1 9 0 2h V 1 1 0 3 PYRIDOSTIGMINE O N F 14±3% CL 8.5±1.7 Cholinergic, does not cross bbb pb Low Mwt 181.2 Metabolite: O N ur 85±5% PSA 33.4 A˚ 2 3-hydroxy-N-methylpyridinium log P −3.93

1/ t 2 69 h V – DISTIGMINE O N N O F 5% CL – Cholinesterase inhibitor pb – Mwt 416.5 O O N N ur 7% PSA 66.9 A˚ 2 log P −5.29

1/ / t 2 3–8 h V F 0.5–1.3 PYRIDINOL CARBAMATE H H F –CL–Antiarteriosclerotic N O O N pb – Mwt 253.3 N Metabolism: demethylation ur – PSA 89.6 A˚ 2 O O log P 0.24

1/ t 2 4–6 h V – NICOTINAMIDE O F –CL–VITAMIN B3 pb – Mwt 122.12 Metabolism: N-methylation of NH2 ur – PSA 56 A˚ 2 pyridine, then addition of water at − . N log P 0 37 position 4 and para to carbamoyl group

t1/ 9±2h V/F 0.70±0.09 PYRAZINAMIDE O 2 F 100% CL/F 0.90±0.15 Tuberculostatic, crosses bbb N pb 10–50% Mwt 123.11 NH2 Metabolite: pyrazinecarboxylic acid ur 0–3% PSA 68.9 A˚ 2 N log P −0.71

t1/ 0.5 h V – NIKETHAMIDE O 2 F –CL–Respiratory stimulant N pb – Mwt 178.2 Metabolism: N-dealkylation ur – PSA 33.2 A˚ 2 N log P 0.92

1/ . ± . t 2 1–3 h V 0 67 0 15 ISONIAZIDE O ∗ F –CL7.4±2.0 ∗Fast acetylators; slow acetylators: NH2 N pb 0–15% Mwt 137.1 3.7±1.1; antibacterial, hepatotoxic H N ur 10–30% PSA 68.0 A˚ 2 Metabolism: N-acetylation log P −0.77 (continued overleaf ) 400 59 Pyridines, Pyrimidines, and Related Compounds

t1/ 10 h V – IPRONIAZID O 2 H F –CL–MAO inhibitor, antidepressant N N pb – Mwt 179.2 Metabolite: 4-pyridinecarboxylic acid H ˚ 2 N ur 15% PSA 54.0 A log P 0.41

1/ O t 2 1.3 h V 0.6–1.7 PIROXIMONE H F >80% CL 7–9 Inotropic N pb 85% Mwt 217.2 Metabolism (dog): reduction of O ˚ 2 N N ur 64% PSA 71.1 A ketone to alcohol, oxidative cleavage H log P 2.15 to isonicotinic acid

1/ t 2 1.5–3.0 h V 3.4 PINACIDIL F 60% CL 9.5 Potassium channel opener, H H N N pb 60–65% Mwt 245.3 antihypertensive ur 4–10% PSA 73.1 A˚ 2 Metabolism: N-oxidation of pyridine N N log P 2.31 (t1/ N-oxide: 2.5 h), hydroxylation of CN 2 t-Bu, N-dealkylation

1/ O F t 2 12–20 h V – ROFLUMILAST Cl H F 69–92% CL – PDE4 inhibitor, bronchodilator N F pb 99% Mwt 403.2 O Metabolite: pyridine N-oxide ur – PSA 60.5 A˚ 2 N O Cl log P 2.31

1/ O F t 2 14–30 h V – OGLEMILAST Cl > ∗ ∗ H F 50% CL – mice N F pb – Mwt 516.3 PDE4 inhibitor O ur – PSA 119 A˚ 2 N O Metabolite: pyridine N-oxide Cl log P 4.56 O O S N H

1/ . ± . . ± . t 2 1 9 0 3h V 1 4 0 3 ETHIONAMIDE S F 100% CL – Tuberculostatic pb 10–30% Mwt 166.2 Metabolism: S-oxidation, conversion NH2 ur <1% PSA 71.0 A˚ 2 to carboxamide, reduction of N log P 1.17 thioamide to hydroxymethyl

1/ S t 2 1.4 h V – PROTIONAMIDE F –CL–Tuberculostatic NH2 pb – Mwt 180.3 Metabolism: S-oxidation, conversion N ur <1% PSA 71.0 A˚ 2 to carboxamide and carboxylic acid, log P 1.68 N-methylation 401

1/ N t 2 0.5–2.5 h V – METYRAPONE, METOPYRONE O F –CL–Oral diagnostic aid pb – Mwt 226.3 Metabolism: reduction of ketone to ur <1% PSA 42.9 A˚ 2 alcohol N log P 1.14

1/ O t 2 0.8–1.5 h V 0.5–1.4 NICORANDIL F 75% CL 7.3–16.4 Antianginal O N NO pb 24% Mwt 211.2 Metabolism: hydrolysis to nicotinic H 2 ur <1% PSA 97.0 A˚ 2 acid N log P 0.74

t1/ 8–9 h V 3.6±0.6 LAZABEMIDE O 2 F 78% CL – MAO inhibitor N NH2 N pb – Mwt 199.6 Metabolism: oxidation of CH2NH2 to H ur – PSA 68.0 A˚ 2 CO H Cl 2 log P 0.20

1/ t 2 5–7 h V 2.3 PROPIRAM F >97% CL 6.3 Analgesic, narcotic; N N N pb – Mwt 275.4 Metabolism: piperidine ur 24% PSA 36.4 A˚ 2 hydroxylation, then oxidation to O log P 3.01 lactam, then hydrolysis of lactam

1/ t 2 3–4 h V – BETAHISTINE F 100% CL – Vasodilator, antivertigo, histamine pb 0–5% Mwt 136.2 agonist N N ˚ 2 H ur 0% PSA 24.9 A Metabolites: desmethyl and log P −0.02 2-pyridylacetic acid

1/ t 2 3–9 h V – ISPRONICLINE H F –CL–Nicotinic acetylcholine partial O N pb – Mwt 234.3 agonist, nootropic ur – PSA 34.2 A˚ 2 Metabolism: O-dealkylation, N log P 2.47 N-demethylation, pyridine N-oxidation, oxidative degradation of side chain

1/ t 2 5–7 h V 0.3–0.6 SARIZOTAN F 89% CL 0.7 5-HT1A agonist for treatment of F pb >99.9% Mwt 348.4 dyskinesia ur <5% PSA 34.2 A˚ 2 Metabolism: aromatic hydroxylation O N log P 4.38 (para to O), hydroxylation at H CH2CH2, N-de(pyridylmethylation), N then oxidation to pyridine-3-carboxylic acid and chroman-2-carboxylic acid (continued overleaf ) 402 59 Pyridines, Pyrimidines, and Related Compounds

1/ O t 2 12 h V – TEMELASTINE Br F High CL – Histamine H1 antagonist; does not N pb >99% Mwt 442.4 cross bbb < . 2 N HN N N ur 0 2% PSA 79.3 A˚ Metabolism: N-glucuronidation H log P 3.76

1/ t 2 2h V 0.8 LAFUTIDINE O F –CL4 Histamine H2 antagonist pb – Mwt 431.6 N O Metabolism: hydroxylation, oxidation S ˚ 2 H ur – PSA 104 A to sulfone N log P 2.24 O N O

1/ . ± . . ± . t 2 2 0 0 7h V 2 6 0 9 NICOTINE ∗ F 30%∗ CL 18.5±5.4 pulmonal: 90% pb 5±3% Mwt 162.2 Tobacco alkaloid N ur 17±9% PSA 16.1 A˚ 2 Metabolism: N-demethylation (to H 1/ log P 0.57 nornicotine, t 2 7–9 h), N-oxidation N and hydroxylation of pyrrolidine, N-methylation of pyridine, conversion to cotinine

1/ t 2 12–16 h V 0.9 COTININE F 84–100% CL 0.9 Metabolite of nicotine O pb – Mwt 176.2 Metabolism: N-methylation and N 2 H ur 12% PSA 33.2 A˚ oxidation of pyridine, hydroxylation N log P 0.08 of pyrrolidinone, demethylation, glucuronidation

1/ ∗ OH t 2 4–10 h V 0.5–1.1 3-HYDROXYCOTININE F – CL 1.1–2.6 ∗iv O pb – Mwt 192.2 Metabolite of cotinine N ur – PSA 53.4 A˚ 2 H log P −1.12 N

1/ OMe t 2 18 h V – PENCLOMEDINE F 49±18% CL – Cl Cl Antineoplastic pb – Mwt 325.4 Metabolism: demethylation Cl ur – PSA 31.4 A˚ 2 MeO N Cl log P 5.26 Cl

1/ Cl Cl t 2 5h V – TRICLOPYR F –CL–Herbicide pb – Mwt 256.5 Cl N O CO2H ur 80% PSA 59.4 A˚ 2 log P 2.35 403

1/ t 2 1.2 h V – OXISURAN F –CL–Immunosuppressor N S pb – Mwt 183.2 Metabolism: reduction of ketone to < ˚ 2 1/ O O ur 1% PSA 66.2 A alcohol (t 2 55 h) log P 0.02

1/ HO OH t 2 2–3 h V – PYRITINOL F –CL–Nootropic HO OH pb – Mwt 368.5 S S ur – PSA 157 A˚ 2 N N log P 0.64

1/ O t 2 5–18 h V 0.6 CICLETANINE F 75% (rat) CL – Antihypertensive HO Cl pb 97% Mwt 261.7 Metabolism: glucuronidation, ur <1% PSA 42.4 A˚ 2 sulfation N log P 1.78

1/ ± ∗ t 2 7 2h V – BESIPIRDINE ± ∗ ∗ N F –CL217 monkey N pb – Mwt 251.3 Nootropic ∗ ur 1% PSA 21.1 A˚ 2 Metabolism: N-depropylation log P 4.18 N

1/ t 2 1–3 h V 2 (rat) LINOPIRDINE F <10% (rat) CL 0.6 CNS stimulant, nootropic pb – Mwt 391.5 Metabolism: N-oxidation O N ur Negligible PSA 46.1 A˚ 2 log P 1.95 N

1/ O O t 2 21–27 h V 1.6–1.7 ETORICOXIB S F 100% CL 0.7–0.8 Antiinﬂammatory, analgesic pb 92% Mwt 358.8 Metabolism (CYP3A4): oxidation of Cl ur <1% PSA 68.3 A˚ 2 methylpyridine to hydroxymethyl- log P 2.21 and carboxypyridine N

(continued overleaf ) 404 59 Pyridines, Pyrimidines, and Related Compounds

1/ ∗ t 2 8h V – PERAMPANEL ∗ F 75% CL – ∗monkey NC pb – Mwt 349.4 AMPA antagonist, antiepileptic O ur – PSA 57.0 A˚ 2 log P 3.70 N

1/ O t 2 0.8–3.2 h V 0.67 CADRALAZINE H > HO N F 80% CL 4.4 Antihypertensive N O pb 26% Mwt 283.3 Metabolism: hydrolysis of carbamate H N ur 70–80% PSA 99.6 A˚ 2 N N log P 0.54

1/ H t 2 7–12 h V 6.2 RETIGABINE, EZOGABINE N O F 60% CL 11 Anticonvulsant O pb 80% Mwt 303.3 Metabolism: N-acetylation, ˚ 2 N NH2 ur 36% PSA 76.4 A N-glucuronidation H log P 0.96 F

1/ H t 2 8.5 h V 1.2 FLUPIRTINE N O F 90%∗ CL 1.6 ∗rectal: 72% O pb 80% Mwt 304.3 Analgesic, crosses bbb ˚ 2 N N NH2 ur 15% PSA 89.3 A Metabolism: carbamate hydrolysis, H log P 1.60 then N-acetylation F

1/ t 2 32–35 h V 1.5 BRODIMOPRIM MeO F 80–90% CL 0.6 Antibacterial N pb 93% Mwt 339.2 Metabolism: N-oxidation, Br N NH ur 4–7% PSA 96.3 A˚ 2 hydroxylation of methylene group, H2N 2 MeO log P 2.29 O-demethylation, then O-glucuronidation and sulfation

1/ ± . ± . t 2 10 2h V 1 6 0 2 TRIMETHOPRIM MeO F 100% CL 1.9±0.3 Inhibitor of dihydrofolate N pb 37±5% Mwt 290.3 biosynthesis, antibacterial ur 63±10% PSA 106 A˚ 2 Metabolism: O-demethylation, then MeO H N N NH2 2 log P 0.59 oxidation to o-quinones, p-quinone MeO methides, and iminoquinone methides 405

1/ t 2 2–4 h (iv) V 1.3–1.7 ICLAPRIM F 41% CL 7.8–9.2 Antibacterial O pb 92–94% Mwt 354.4 Metabolism: O-demethylation, N ur 2% PSA 106 A˚ 2 oxidative ring scission of pyran, log P 2.20 dihydroxylation of alkene, MeO H N N NH2 2 N-oxidation, glucuronidation MeO

1/ t 2 43–75 min V – PHENAZOPYRIDINE F >60% CL – Analgesic N N pb – Mwt 213.2 Metabolism: phenyl 2- and ur 65% PSA 89.7 A˚ 2 4-hydroxylation, reductive cleavage of H2N N NH2 log P 2.21 N=Nbond

1/ ± / . ± . Cl t 2 81 32 h V F 2 3 0 6 PYRIMETHAMINE F 100% CL/F 0.41±0.06 Antiprotozoal pb 87±1% Mwt 248.7 N Metabolite: N-oxide ur 65% PSA 77.8 A˚ 2

H2N N NH2 log P 2.75

1/ Cl t 2 12–15 h V – CYCLOGUANIL F –CL–Active metabolite of proguanil pb – Mwt 251.7 N N ur – PSA 80.0 A˚ 2

H2N N NH2 log P 0.95

1/ Cl t 2 18–37 h V 0.9–1.3 LAMOTRIGINE Cl F 100% CL 0.35–0.60 Anticonvulsant pb 40–60% Mwt 256.1 Metabolites: N-glucuronide, N-oxide, N ur 5–10% PSA 90.7 A˚ 2 N-methyl N log P 1.24

H2N N NH2

1/ NC t 2 36–48 h V – RILPIVIRINE ∗ F 100% CL – ∗dog CN N pb 99.7% Mwt 366.4 Antiviral (HIV) ur <1% PSA 97.4 A˚ 2 N N N H H log P 3.63

t1/ 30–40 h V 6.5 ETRAVIRINE NH2 2 Br NC CN F –CL–Antiviral (HIV) N pb 99.9% Mwt 435.3 Metabolism: hydroxylation of methyl ˚ 2 O N N ur 0% PSA 121 A followed by glucuronidation H log P 4.19

(continued overleaf ) 406 59 Pyridines, Pyrimidines, and Related Compounds

1/ t 2 31 h V 0.3 PAZOPANIB N N F 14–39% CL 1.4 Tyrosine kinase inhibitor, N pb >99% Mwt 437.5 antiangiogenic NH ur <4% PSA 127 A˚ 2 N N N S 2 H O O log P 1.98

1/ t 2 2.2–2.4 h V – REVAPRAZAN, YH1885 F F 40% (rat) CL – Proton pump inhibitor, antiulcerative N pb – Mwt 362.4 N N N ur 0% PSA 41.1 A˚ 2 H log P 5.29

1/ t 2 2–5 h V – MINAPRINE F 5% (rat) CL – Antidepressant O pb – Mwt 298.4 Metabolism: aromatic 2 N N ur Trace (rat) PSA 50.3 A˚ 4-hydroxylation, N-oxidation, N N H log P 2.04 N-dealkylation

t1/ 1.4–5.8 h V 1.3±0.3 AMRINONE N 2 F 93±12% CL 2.4–11.6 Phosphodiesterase III inhibitor, NH 2 pb 35–49% Mwt 187.2 cardiotonic ur 10–40% PSA 68.0 A˚ 2 Metabolism: N-acetylation, N O − . H log P 0 21 N-acylation with glycolic acid

t1/ 0.8±0.2h V 0.32±0.08 MILRINONE N 2 F 80–92% CL 6.1±1.3 Phosphodiesterase III inhibitor, CN pb 85±10% Mwt 211.2 cardiotonic ur 85±10% PSA 65.8 A˚ 2 Metabolism: O-glucuronidation N O H log P 1.27

1/ OH t 2 1.7 h V – CICLOPIROX F –CL–Antifungal N O pb 96% Mwt 207.3 Metabolism: glucuronidation ur 6% PSA 40.5 A˚ 2 log P 2.57

1/ t 2 2–3 h V – PIRFENIDONE F 56% (dog) CL – Antiﬁbrotic N pb 58% Mwt 185.2 Metabolism: oxidation of methyl to ur <1% PSA 20.3 A˚ 2 carboxyl O log P 1.82 407

1/ t 2 9–13 h V 2–3 AMEZINIUM F 40–74% CL – Antihypotensive N N pb – Mwt 202.2 Metabolism: O-demethylation (to ur 32% PSA 52.0 A˚ 2 uncharged pyridazin-2-one), then MeO NH2 log P −1.76 hydroxylation and conjugation

1/ . ± . / . ± . t 2 3 1 0 6h V F 2 7 0 7 MINOXIDIL F 90% CL/F 24±6 Potassium channel opener, pb 0% Mwt 209.3 antihypertensive, antialopecia agent N N NH2 ur 20±6% PSA 93.6 A˚ 2 Metabolism: O-sulfation, N log P 1.62 glucuronidation, 3- and O 4-hydroxylation of piperidine, NH2 oxidative ring-opening of piperidine (to 4-carboxybutylamino), reductive N−O bond cleavage

1/ Cl t 2 6d V – IRSOGLADINE F –CL–Antiulcerative N NH pb – Mwt 256.1 Cl 2 Metabolism: N-oxidation ur 1.4% PSA 90.7 A˚ 2 NN log P 2.08

NH2

1/ / F t 2 5–12 h V F 0.4 RIOCIGUAT F –CL/F 0.4 Guanylate cyclase stimulator for pb – Mwt 422.4 treatment of pulmonary hypertension ˚ 2 N N ur – PSA 138 A log P −0.31 N N NH2 N CO Me N 2

NH2

1/ t 2 4.3–7.3 h V 0.2 BOSENTAN F 43–50% CL 1.4–2.8 Antihypertensive O pb 96–98% Mwt 551.6 CYP2C9 and CYP3A4 inducer 2 N O S ur <1% PSA 154 A˚ Metabolism: hydroxylation of t-Bu, N NH log P 1.15 O-demethylation N N O O OMe HO

(continued overleaf ) 408 59 Pyridines, Pyrimidines, and Related Compounds

t1/ 13–18 h V – MACITENTAN O H 2 N F 80%∗ CL – ∗ O S dog pb 99%∗ Mwt 588.3 N NH Endothelin antagonist ˚ 2 1/ ur – PSA 137 A Metabolite: despropyl (t 2 45–66 h) Br N log P 5.41 N O N O Br

1/ ± NH O t 2 6–10 h V 17 4AMILORIDE F 50% CL 9.7±1.9 N Cl Diuretic H2N N pb 40% Mwt 229.6 H ur 49±10% PSA 157 A˚ 2 H2N N NH2 log P 0.93

1/ t 2 7h V – SAPROPTERIN H H ∗ N N NH F 10%∗ CL – animals OH 2 pb Low Mwt 241.3 Essential enzymatic cofactor; N 2 N ur – PSA 132 A˚ treatment of phenylketonuria H H − . HO O log P 4 22 Metabolites: dihydrobiopterin, biopterin

1/ . ± . . ± . t 2 4 2 0 7h V 13 4 4 9 TRIAMTERENE H2N N N NH2 F 54±12% CL 63±20 Diuretic N pb 61±2% Mwt 253.3 Metabolism: hydroxylation, N ur 52±10% PSA 130 A˚ 2 glucuronidation, sulfation NH2 log P 1.16

t1/ 3.1±1.2h V – HYDROXYTRIAMTERENE H2N N N NH2 2 F –CL2.3±0.6 SULFATE N pb 90±1% Mwt 349.3 O O N Active metabolite of triamterene ur – PSA 202 A˚ 2 S NH2 HO O log P −0.13

1/ . ∗ N N NH t 2 2–6 h V 1 8 PIRITREXIM OMe 2 ∗ ∗ H F 75–95% CL 10 dog N N pb – Mwt 325.4 Antineoplastic ∗ ur <3% PSA 109 A˚ 2 Metabolism: O-demethylation NH2 log P 1.97 OMe 409

t1/ 12–20 h V 0.6–0.8 TRIMETREXATE N NH2 2 H F 44% CL 0.4–0.7 Antineoplastic MeO N N pb 98% Mwt 369.4 Metabolism: O-demethylation, then ur <5% PSA 118 A˚ 2 glucuronidation, sulfation NH2 MeO log P 1.76 OMe

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; bbb, blood–brain barrier; CNS, central nervous system; MAO, monoamine oxidase; NAD, nicotine–adenine- dinucleotide; PDE, phosphodiesterase.

Table 59.2 Proton pump inhibitors and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

t1/ 0.9–2.1 h V 0.28–0.45 LANSOPRAZOLE O N 2 H F 81–91% CL 2.6–7.4 Racemic, proton pump inhibitor, S N pb 97–99% Mwt 369.4 antiulcerative O CF3 < 2 N ur 2% PSA 87.1 A˚ Metabolism by CYP3A4 and log P 2.58 CYP2C19 to sulfone and 5-hydroxybenzimidazole

t1/ 1–2 h V 0.22 RABEPRAZOLE O N 2 H F 52% CL 4.3–8.4 Racemic, proton pump inhibitor, S N O pb 95–98% Mwt 359.4 antiulcerative 2 N ur 0% PSA 96.3 A˚ Metabolism: demethylation, MeO log P 2.10 oxidation to sulfone, reduction to thioether

t1/ 0.7±0.5h V 0.34±0.09 OMEPRAZOLE O N 2 H F 53±29% CL 7.5±2.7 Racemic, proton pump inhibitor, S N OMe pb 95% Mwt 345.4 antiulcerative N ur <0.1% PSA 96.3 A˚ 2 Metabolism by CYP2C19 and CYP3A log P 2.36 to 5-(hydroxymethyl), sulfone, O-desmethyl MeO (5-hydroxybenzimidazole)

1/ O N t 2 5–8 h V – TENATOPRAZOLE H F 77–88% CL – Racemic, proton pump inhibitor, N S OMe pb – Mwt 346.4 antiulcerative N ur – PSA 104 A˚ 2 Metabolites: sulﬁde, sulfone N log P 346.4 MeO

(continued overleaf ) 410 59 Pyridines, Pyrimidines, and Related Compounds

1/ O N t 2 0.9–1.9 h V 0.17 PANTOPRAZOLE H F 67–89% CL 2.2 Racemic, proton pump inhibitor, N S OMe pb 98% Mwt 383.4 antiulcerative N OMe ur Negligible PSA 106 A˚ 2 Metabolism: oxidation to sulfone, F log P 1.57 reduction to thioether, demethylation O followed by sulfation F

t1/ 4–9 h V/F 1.7–2.5 ILAPRAZOLE O N 2 H F –CL/F 2.4–3.0 Racemic, proton pump inhibitor, N S OMe pb – Mwt 366.4 antiulcerative N ur – PSA 92.0 A˚ 2 Metabolism: oxidation to sulfone, N log P 2.66 reduction to sulﬁde, hydroxylation of pyrrole

1/ O t 2 1.4 h V 2–3 ISOMAZOLE S F – CL 19–24 Cardiotonic H pb – Mwt 287.3 Metabolism: oxidation to sulfone, N ur – PSA 87.1 A˚ 2 hydroxylation log P 1.14 N OMe N

t1/ 2.2±0.4h V 0.54±0.09 ZOLPIDEM N 2 F 67±20% CL 4.3±2.2 Sedative, hypnotic; CYP3A4 substrate pb 92% Mwt 307.4 O Metabolism: benzylic hydroxylation, < 2 ur 1% PSA 37.6 A˚ then oxidation of CH2OH to CO2H N log P 3.07 N

1/ t 2 18–20 h V 5 (rat) ALPIDEM N F 13% (rat) CL – Anxiolytic Cl pb 99% Mwt 404.3 Metabolism: N-dealkylation, 2 O ur 0% PSA 37.6 A˚ hydroxylation of CH2Me; withdrawn N log P 5.49 in 1996 because of hepatotoxicity Cl N

1/ t 2 1h V 0.18–0.23 FAZADINIUM F – CL 1.9–2.3 Muscle relaxant pb 17% Mwt 444.5 Metabolism: reductive N=Nbond ur 0% PSA 42.8 A˚ 2 cleavage, phenyl 4-hydroxylation N N N N log P −1.44 N N 411

1/ t 2 0.4–1.5 h V 2 PIMOBENDAN OMe F 60–65% CL 14 Cardiotonic H Metabolism: N-glucuronidation, N pb 98% Mwt 334.4 ur – PSA 79.4 A˚ 2 O-demethylation, then O N log P 2.08 O-glucuronidation HN N Active metabolite: O-desmethyl 1/ (t 2 2h)

1/ t 2 0.8–1.8 h V 0.28 SIMENDAN F 85±6% CL 4 Calcium sensitizer for treatment of CN pb 98% Mwt 280.3 N congestive heart failure; ˚ 2 O N CN ur 0% PSA 113 A levosimendan has similar PK HN N H log P 1.02 Metabolism: reduction to 4-aminophenyl, then N-acetylation

1/ O t 2 5–10 h V 16–87 OLAPARIB ∗ F 100% CL 0.3–2.4 ∗rat, dog N pb – Mwt 434.5 PARP inhibitor, antineoplastic N N 2 O N F ur – PSA 82.1 A˚ H O log P 0.00

60 Quinolines

The quinoline substructure is not essential in all quinoline-containing drugs (Table 60.1). Substituted quinolines and quinazolines are, however, much easier to synthesize and metabolically less questionable than, for instance, substituted naphthalenes. The most important quinoline-derived drugs are antimalarials, quinolone antibacterials, and the ‘‘tecan’’ antineoplastics. In these drugs, the quinoline substructure is an essential pharmacophore and cannot be replaced by other heteroarenes. In other drugs, however, the quinoline substructure just acts as lipophilic substituent or as scaffold and may be replaced by isoquinolines, quinazolines, or related heteroarenes. Thus, although most antineoplastic tyrosine kinase inhibitors are quinazolines, such as geﬁtinib, a quinoline scaffold can yield compounds with similar biological activity (e.g., bosutinib, Scheme 60.1).

MeO N MeO N

N N O CN N O N MeO NH O Cl NH

Cl Cl F Bosutinib (tyrosine kinase inhibitor) Gefitinib (tyrosine kinase inhibitor) − − t1/2 17 21 h, F 18% t1/2 34 65 h, F 59%

Scheme 60.1 Quinolines versus quinazolines.

Few drugs (mainly topical antifungals) contain unsubstituted naphthyl groups, which may hint at toxic metabolites. Quinolines, being less electron rich, are not readily metabolized to arene oxides and may, therefore, be safe bioisosteres of naphthyl groups.

The antimalarial properties of extracts from the chinchona bark were already known in the seventeenth century. The active principle, quinine, was isolated in 1820 by Pelletier and Caventou and used as antimalarial since then. In the 1930s, cheaper, more readily accessible antimalarials were sought, and thousands of acridine and quinine analogs were prepared and tested. Interestingly, chloroquine (Scheme 60.2) was independently discovered by German (1934) and American chemists (1943) and became one of the most successful antimalarial drugs. Quinoline-derived antimalarials have high oral bioavailabilities and long half-lives and can be used for years without serious side effects.

HO N N HN H MeO

N Cl N Quinine Chloroquine t1/2 11 h, F 76% t1/2 41 d, F 89%

Scheme 60.2 Antimalarial quinolines.

Chloroquine is highly toxic to malaria schizonts, the pre-erythrocytic stage of the malaria parasite Plasmodium falciparum. The drug is assumed to act by inhibiting the parasites digestion of hemoglobin and by fragmenting and intercalating into its nucleic acids. Some malaria strains have become chloroquine resistant, and new drugs and treatment regimes are constantly being developed [1]. Quinolines are metabolically stable, and degradation in vivo takes place only at the substituents. Only quinolines substituted with electron-donating groups may undergo aromatic hydroxylation in vivo. The long half-life of chloroquine is mainly due to its extensive distribution into all kinds of tissue (volume of distribution: 100–1000 l kg−1). Illustrative examples of quinoline metabolism are sketched in Scheme 60.3. 414 60 Quinolines

H N N HN HN NH2 in vivo +

Cl N Cl N Cl N Chloroquine Desethylchloroquine t1/2 41 d, t1/2 15 d F 89% (+didesethylchloroquine)

NH2 NH2 HN HN NH2 N in vivo N N +

OMe OMe OH Primaquine OH OH − t1/2 3 8 h, F > 95%

HO N CO2H H in vivo

N CF3 N CF3 CF3 CF3 Mefloquine t1/2 20 d

OH OH OH

Ar O HN HN N in vivo H N HN + O Ar Cl N Cl N N Amodiaquine Monodesethylamodiaquine HN t 5 min − 1/2 t1/2 9 18 d

NH2 NH2 OH

in vivo in vivo Further hydroxylation N N Tacrine Velnacrine − t1/2 2.7 h, F 17% t1/2 2 3 h

Scheme 60.3 Metabolism of quinolines. 60.2 Quinazolines 415

60.1 Tecans

The antineoplastic properties of the tree Camptotheca acuminata were discovered 1958, and the active alkaloid camptothecin was isolated 1966 at the Research Triangle Institute (NC). This compound does not readily dissolve in water (0.0025 mg ml−1), not even as sodium salt of the saponiﬁed lactone. Despite its new and promising biological activity (topoisomerase I inhibition [2]), the compound could not be advanced to phase II clinical trials because of poor solubility and excessive toxicity. In the 1980s, the National Cancer Institute (USA) and SmithKline Beecham provided camptothecin to the University of Florida at Gainsville, where a team headed by Warren Ross developed a soluble, semisynthetic analog of camptothecin: topotecan (Scheme 60.4). The remaining development was carried out by SmithKline Beecham, and topotecan was ﬁnally launched in 1996 for the treatment of ovarian and small cell lung cancer. Since then, a number of additional camptothecin analogs were successfully developed [3] (Table 60.2).

O HO O N N N N O O

OH O OH O Camptothecin topotecan Solubility: 0.0025 mg ml–1 t ½ 2−8 h, F 34−44% Solubility(HCl salt): 1 mg ml–1

Scheme 60.4 Improvement of the solubility of camptothecin.

60.2 Quinazolines

Structurally closely related to quinolines are the quinazolines, the substructure of various important classes of drugs. These include α1-adrenergic antagonists (e.g., prazosin), tyrosine kinase inhibitors (e.g., erlotinib), and some antifolates. The quinazoline and quinoline substructures can often be interchanged, with rough retention of biological activity. Other heterocycles that may be used as an alternative to quinolines or quinazolines include pteridines and naphthyridines (Scheme 60.5). Quinazolines are, however, often easiest to prepare (from anthranilic acid derivatives). 416 60 Quinolines

N N N N

N N N N N N N Quinoline Quinazoline1,5-Naphthyridine 1,8-Naphthyridine Pteridine mp −15 °C 48 °C 73 °C 98 °C 138 °C bp 237 °C 241 °C 265 °C

Scheme 60.5

α1-Adrenergic antagonists lead to a general vasodilation and are mainly used as antihypertensives and for the treatment of benign prostatic hyperplasia (Table 60.3). Main metabolic pathways include O-demethylation of methoxy groups and N-dealkylation of amines.

References

1. O’Neill, P.M., Bray, P.G., Hawley, S.R., Ward, S.A., and Park, B.K. (1998) 4-Aminoquinolines – past, present, and future: a chemical perspective. Pharmacol. Ther., 77, 29–58. 2. Pommier, Y. (2009) DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem. Rev., 109, 2894–2902. 3. Verma, R.P. and Hansch, C. (2009) Camptothecins: a SAR/QSAR study. Chem. Rev., 109, 213–235.

Table 60.1 Quinolines and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

1/ H t 2 5–9 h V 1.7 AMSACRINE MeO N F Low CL 4.3 Antineoplastic S pb 97% Mwt 393.5 O O Metabolism: glucuronidation, HN ur 20%(iv) PSA 88.7 A˚ 2 oxidation to quinoneimine log P 3.32

1/ H t 2 2.4 h V 0.3 ASULACRINE MeO N F –CL2.6Topoisomerase II inhibitor, S pb >99% Mwt 464.5 antineoplastic O O HN ur – PSA 118 A˚ 2 Metabolism: oxidative thiolation log P 0.46 with glutathione (meta to OCH3)

O N H 417

1/ t 2 16–17 d V 4.6 PYRONARIDINE N F 20% CL 5–7 Antimalarial pb – Mwt 518.1 Metabolism: dehydrogenation of OH ur 1% PSA 73.8 A˚ 2 aminophenol to quinoneimine, log P 4.86 O-demethylation, hydroxylation N HN N OMe

Cl N

1/ Cl t 2 70 d V – CLOFAZIMINE F 45–62% CL – Tuberculostatic pb – Mwt 473.4 Metabolism: hydratation, ur <1% PSA 40.0 A˚ 2 hydroxydechlorination, hydrolytic log P 7.46 deamination, then glucuronidation N N Cl

N N H

1/ t 2 24 h V – TMC-207 F Reasonable CL – Tuberculostatic pb – Mwt 555.5 Metabolite: N-monodesmethyl N ur – PSA 45.6 A˚ 2 OH log P 7.71 Br Ph

N OMe

1/ Cl t 2 11–14 h V – CLIOQUINOL F 11–32% CL – Treatment of Alzheimer’s disease, pb – Mwt 305.5 chelator (Zn, Cu), crosses bbb ur Traces PSA 33.1 A˚ 2 Metabolite: glucuronide; withdrawn I N log P 4.17 in 1973 for causing neurotoxicity OH

1/ I t 2 11–14 h V – IODOQUINOL F 8% CL – Antiamebic pb – Mwt 397.0 ur – PSA 33.1 A˚ 2 I N log P 4.10 OH

1/ Cl t 2 7h V – CHLORQUINALDOL F –CL–Antibacterial pb – Mwt 228.1 Metabolite: glucuronide ur <1% PSA 33.1 A˚ 2 Cl N log P 3.51 OH

(continued overleaf ) 418 60 Quinolines

1/ O O t 2 1.5–2.0 h V 0.8 FLOSEQUINAN F 72% CL 8.2 S Vasodilator, antihypertensive pb – Mwt 239.3 Active metabolite: sulfone ur 1% PSA 56.6 A˚ 2 (t1/ 30–40 h) F N 2 log P −1.43

1/ t 2 35–40 h V – TALNETANT F High CL – NK3 antagonist for treatment of pb – Mwt 382.5 schizophrenia HN O ur – PSA 62.2 A˚ 2 log P 5.80 OH

1/ t 2 2.5 h V 5IMIQUIMOD N F 47% CL 16 Antiviral, immunomodulator N pb – Mwt 240.3 Metabolism: glucuronidation, ur <1% PSA 56.7 A˚ 2 aromatic and aliphatic log P 3.01 hydroxylation, N-oxidation N NH2

1/ t 2 9–14 h V 4 852 A F 27% CL 16 S NH N Immunomodulator N pb – Mwt 361.5 O O ur – PSA 111 A˚ 2 log P 1.89 N NH2

1/ O t 2 10–17 h V 0.15 AZAPROPAZONE F 83±19% CL 0.14 Antiinﬂammatory, metabolized by N O pb 99.5% Mwt 300.4 CYP2C9 N ur 63% PSA 56.2 A˚ 2 Metabolite: 8-hydroxy N N log P 1.78

t1/ 2.5±0.9h∗ V – NOLATREXED, AG-337 N 2 F >95% CL 2–6 ∗iv S O pb – Mwt 284.3 Thymidylate synthase inhibitor, ∗ ur 9–35% PSA 106 A˚ 2 antineoplastic NH log P 2.10

N NH2 419

1/ t 2 20–60 h V 6 METHAQUALONE O F –CL1.7Metabolites: 4 -hydroxy, N-oxide, pb 70–90% Mwt 250.3 2 -hydroxymethyl, 3 -hydroxy, N ur Negligible PSA 32.7 A˚ 2 6-hydroxy, 2-hydroxymethyl; N log P 2.50 withdrawn in 1984 for causing addiction

t1/ 3.3 h V – AFLOQUALONE O 2 F –CL–Muscle relaxant, crosses bbb H N 2 N pb – Mwt 283.3 Metabolites: N-acetyl, 2 F ur 4% PSA 58.7 A˚ N-acetyl-2 -hydroxymethyl, N log P 0.85 N-glucuronide

1/ t 2 0.6–1.3 h V 0.15 PROQUAZONE F 6–8% CL 9.5 Antiinﬂammatory pb >98% Mwt 278.4 Metabolism: aromatic ur Negligible PSA 32.7 A˚ 2 3-hydroxylation, then conjugation N log P 3.16 N O

t1/ 0.8 h (iv) V 0.6 TIRAPAZAMINE O 2 F 75% CL 8.9 Hypoxia-selective antineoplastic N N pb 19% Mwt 178.2 Metabolism: reductive cleavage of ur 14–53% PSA 89.8 A˚ 2 N−O bonds N NH2 log P −0.29 O

1/ . ± . . ± . t 2 1 0 0 3h V 1 5 1 0 HYDRALAZINE F 10–40% CL 56±13 Antihypertensive NH2 HN pb 87% Mwt 160.2 Metabolism: N-acetylation and ur 1–15% PSA 62.8 A˚ 2 cyclization, N-formylation and N log P 0.95 cyclization, aromatic hydroxylation, N substitution of hydrazine by hydroxyl

t1/ 2–5 h V 2.2 ENDRALAZINE NH2 2 HN F 74–99% CL 12–13 Antihypertensive pb – Mwt 269.3 Metabolism: hydrazone formation N ur – PSA 83.1 A˚ 2 with pyruvate and α-ketoglutarate N log P −0.27 N

(continued overleaf ) 420 60 Quinolines

1/ . ± . . ± . t 2 2 7 0 9h V 5 9 3 0TACRINE NH2 F 17±3% CL 36±18 Acetylcholinesterase inhibitor, pb 55% Mwt 198.3 nootropic, crosses bbb ur <1% PSA 38.9 A˚ 2 Metabolism: 1-hydroxylation (to N log P 2.56 velnacrine, see below), 2-, 3-, 4-hydroxylation

t1/ 1.7–2.4 h V – VELNACRINE NH2 OH 2 F –CL–Metabolite of tacrine pb – Mwt 214.3 ur 11–30% PSA 59.1 A˚ 2 N log P 1.47

t1/ 9±4h V – 7-METHOXYTACRINE NH2 2 F –CL– MeO Cholinergic, less hepatotoxic than pb – Mwt 228.3 tacrine ur – PSA 48.1 A˚ 2 N log P 2.45

1/ ± ± t 2 41 14 d V 115 61 CHLOROQUINE F 89±16% CL 1.8±0.4 Antimalarial N ± 1/ ± HN pb 61 9% Mwt 319.9 Metabolites: desethyl (t 2 15 6d), ur 61±4% PSA 28.2 A˚ 2 bisdesethyl, log P 4.41 4-amino-7-chloroquinoline Cl N

1/ t 2 72 h V 76–630 HYDROXYCHLOROQUINE F 44–85% CL – N Antimalarial HN OH pb 50–65% Mwt 335.9 Metabolites: desethyl, ur 16–52% PSA 48.4 A˚ 2 desethylchloroquine log P 3.53 Cl N

1/ t 2 5–14 d V 45 QUINACRINE F Low CL 5.1 Antimalarial, crosses bbb N HN pb 80–90% Mwt 400.0 Metabolism: N-deethylation, then 2 OMe ur – PSA 37.4 A˚ oxidation of CH2NH2 to CO2H, log P 5.59 O-demethylation, N-dealkylation (to Cl N 4-aminoacridine)

1/ t 2 5min V 17–34 AMODIAQUINE OH F –CL–Antimalarial pb 90% Mwt 355.9 Metabolism: N-dealkylation, HN ur 2% PSA 48.4 A˚ 2 oxidation to benzaldehyde and N log P 3.13 quinoneimine Active metabolite: monodesethyl 1/ Cl N (t 2 9–18 d); hepatotoxic, induces agranulocytosis 421

1/ . ± . Cl t 2 4 6 1 1h V 3.3 VATALANIB F 18–57% CL – Antiangiogenic tyrosine kinase HN pb – Mwt 346.8 inhibitor ur 0.4% PSA 50.7 A˚ 2 Metabolism: pyridine N-oxidation, N log P 3.80 aromatic hydroxylation, N hydroxylation of CH2

1/ t 2 3–8 h V 3–8 PRIMAQUINE NH > HN 2 F 95% CL 20 Antimalarial pb – Mwt 259.4 Metabolism: aromatic N ur <1% PSA 60.2 A˚ 2 hydroxylation (para to alkylamino), log P 2.74 O-demethylation, N-dealkylation (to OMe 5,6-dihydroxy-8-aminoquinoline)

1/ / ± t 2 2–3 weeks V F 24 5 TAFENOQUINE NH F –CL0.9±0.2 Antimalarial HN 2 pb – Mwt 463.5 Metabolism: hydroxylation of alkyl MeO N ur – PSA 78.6 A˚ 2 side chain log P 5.81 OMe

O CF3

1/ . ± . . ± . t 2 6 2 1 8h V 2 7 1 2 QUINIDINE ∗ F 80±15%∗ CL 4.7±1.8 sulfate pb 87±3% Mwt 324.4 Antimalarial, antiarrhythmic, HO ur 18±5% PSA 45.6 A˚ 2 CYP3A4 substrate N H log P 2.82 Metabolism: alkene MeO dihydroxylation, oxidation of alcohol to ketone, N-oxidation of N quinuclidine; active metabolite: 1/ ± 3-hydroxyquinidine (t 2 12 3h,pb 60±10%)

1/ ± . ± . t 2 11 2h V 1 8 0 4 QUININE F 76±11% CL 1.9±0.5 Antimalarial, muscle relaxant HO N pb 93±3% Mwt 324.4 H 2 MeO ur 12% PSA 45.6 A˚ log P 2.82 N

(continued overleaf ) 422 60 Quinolines

1/ ± ± t 2 11 4h V 7 2 3-HYDROXYDIHYDRO- F 50–90% CL 12 QUINIDINE HO OH N pb 53% Mwt 340.4 Antiarrhythmic H 2 MeO ur – PSA 65.8 A˚ log P 2.01 N

1/ ± t 2 2 1h(iv) V – CINCHONINE F 44% (rat) CL 39 Antimalarial HO N pb – Mwt 294.4 Metabolism: similar to quinine H ur <10% (iv) PSA 36.4 A˚ 2 log P 2.79 N

1/ ± / ± t 2 20 4d V F 19 6 MEFLOQUINE F –CL/F 0.43±0.14 Racemic, antimalarial, does not HO N pb 98.2% Mwt 378.3 cross bbb H ur <1% PSA 45.2 A˚ 2 log P 2.20

N CF3 CF3

1/ t 2 0.8 h V –FASUDIL O NH F High CL – Kinase inhibitor, vasodilator N O S pb – Mwt 291.4 Metabolism: hydroxylation to ˚ 2 1/ ur – PSA 70.7 A isoquinolin-1-one (t 2 5h) log P 1.72 N

1/ t 2 10–58 h V 6.4 VARENICLINE N F High CL – Nicotinic agonist for treatment of NH pb <20% Mwt 211.3 nicotine addiction N ur 92% PSA 37.8 A˚ 2 Metabolism: glucuronidation, log P 0.74 N-formylation

1/ t 2 2.7–5.5 h V 0.13–0.16 MONTELUKAST HO F 58–66% CL 0.59–0.72 Antiasthmatic pb >99% Mwt 586.2 Metabolism: acyl glucuronidation, Cl N ur <0.2% PSA 95.7 A˚ 2 oxidation to sulfoxide, benyzlic S CO2H log P 7.80 hydroxylation (at CH2),CH3 hydroxylation 423

1/ N t 2 3–5 h V 0.11 VERLUKAST F 100% CL 0.68 Leukotriene D4 antagonist lC N S O pb >99% Mwt 515.1 Metabolism: oxidation to sulfoxide, CO H S 2 2 ur – PSA 121 A˚ hydroxylation of NCH3, then log P 5.93 N-demethylation

Table 60.2 Camptothecin analogs. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ NO2 t 2 15–18 h V 0.8 RUBITECAN ∗ + O F 1–5% (dog) CL 0.4 drug metabolite N pb 97% Mwt 393.4 Topoisomerase I inhibitor, ∗ N ur 10% PSA 126 A˚ 2 antineoplastic, enantiomerically O log P 0.33 pure Active metabolite: OH O 9-aminocamptothecin

1/ NH2 t 2 4–13 h V 2.2 9-AMINOCAMPTOTHECIN F 49% CL 6.5 Antineoplastic, metabolite of O > N pb 99% Mwt 363.4 rubitecan ˚ 2 N ur – PSA 106 A log P 0.75 O

OH O

1/ ± t 2 77 37 h V – GIMATECAN ∗ N F 40–80%∗ CL 0.15±0.10 rat, dog O pb – Mwt 447.5 Topoisomerase inhibitor, O ur <10% PSA 101 A˚ 2 antineoplastic N log P 3.74 Metabolism: hydroxylation of tBu, N glucuronidation, sulfation O

OH O

t1/ 13±4h V 3.6±1.1 KARENITECIN Me Si 2 3 F >40% CL 7.1±4.3 Antineoplastic O pb 99% Mwt 448.6 N ur – PSA 79.7 A˚ 2 N log P 4.46 O

OH O

(continued overleaf ) 424 60 Quinolines

1/ t 2 1.7–8.4 h V 0.4–2.1 TOPOTECAN N F 34–44% CL 2.7–30 Antineoplastic pb 6.6–31% Mwt 421.5 Metabolism: lactone hydrolysis, HO O ur 20–42% PSA 103 A˚ 2 N-demethylation, phenol N log P 1.39 glucuronidation N O

OH O

1/ ∗ N t 2 2–17 h V 0.1–0.4 LURTOTECAN F <6% CL 0.1–1.3 ∗ N iv pb – Mwt 518.6 Antineoplastic ˚ 2 O O ur 15% PSA 105 A N log P 0.97 O N O

OH O

1/ t 2 6–21 h V 2.6–6.3 IRINOTECAN ∗ ∗ mice N F 12–21% CL 5–18 pb 65% Mwt 586.7 Antineoplastic O N ur 10–26% PSA 113 A˚ 2 Metabolism: reversible hydrolysis log P 3.73 of lactone, oxidative ring-opening O O of terminal piperidine to N aminopentanoic acid and N 4-aminopiperidine, hydrolysis of O carbamate to phenol (SN-38; 1/ t 2 8–22 h, pb 95%), then phenol OH O glucuronidation

1/ ∗ t 2 7–8 h V 0.44 EXATECAN NH2 ∗ F –CL0.96iv O pb – Mwt 435.5 Antineoplastic N ur 1–16%∗ PSA 106 A˚ 2 Metabolism: lactone hydrolysis, F N log P 2.13 benzylic hydroxylation (at CH3 and ) O at CH2CH2

OH O

1/ F t 2 2–4 h V 1.3–1.8 DIFLOMOTECAN O F 72–95% CL 6–11 N Antineoplastic pb – Mwt 398.4 Metabolism: reversible lactone F N ˚ 2 O ur 9% PSA 79.7 A hydrolysis log P 2.01 O HO 425

Table 60.3 Quinazolines and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

1/ OMe t 2 3–4 h V 6.3 ABANOQUIL F –CL14α1-Adrenergic antagonist MeO N N OMe pb – Mwt 395.5 ur – PSA 79.1 A˚ 2 MeO log P 3.32 NH2

1/ t 2 5–9 h V 1.5–3.2 ALFUZOSIN MeO N N F 49–100% CL 5.9 α1-Adrenergic antagonist, H pb 82–90% Mwt 389.5 antihypertensive N N MeO O ur 11% PSA 112 A˚ 2 Metabolism: O-demethylation, NH2 O log P −1.00 N-dealkylation, oxidation

1/ ± . ± . O t 2 11 2h V 1 5 0 3 DOXAZOSIN O F 63±14% CL 1.7±0.4 α1-Adrenergic antagonist, N pb 98–99% Mwt 451.5 antihypertensive MeO N N O ur 0.6–1.2% PSA 112 A˚ 2 Metabolism: demethylation, N MeO log P 2.85 aromatic hydroxylation of benzodioxan NH2

1/ O t 2 37–46 h V – VESNARINONE OMe F –CL0.08Cardiotonic N pb 80% Mwt 395.5 Metabolism: oxidation to reactive N 2 OMe ur 19–26% PSA 71.1 A˚ quinone imine, dehydrogenation of log P 1.71 piperazine; causes agranulocytosis O N H

1/ O t 2 2–11 h V 0.8–1.0 DELAVIRDINE F >51% CL – Antiviral (reverse transcriptase O NH N O pb 98% Mwt 456.6 inhibitor) S N HN < ˚ 2 N ur 5% PSA 119 A Metabolism: N-dealkylation, N H log P −1.23 pyridine hydroxylation

1/ . ± . . ± . t 2 2 9 0 8h V 0 60 0 13 PRAZOSIN α F 68±17% CL 3.0±0.3 1-Adrenergic antagonist, O pb 95±1% Mwt 383.4 antihypertensive ur <1% PSA 107 A˚ 2 Metabolism: demethylation, N O log P 2.14 N-dealkylation, glucuronidation, MeO N N amide hydrolysis, hydroxylation of N piperazine, then elimination of MeO water, oxidative degradation of NH2 piperazine, reductive furan opening, then oxidation to 2-oxoglutarate

(continued overleaf ) 426 60 Quinolines

1/ ± . ± . O t 2 12 3h V 0 80 0 18 TERAZOSIN F 90% CL 1.1±0.2 α -Adrenergic antagonist, O 1 N pb 92±2% Mwt 387.4 antihypertensive MeO N N ur 12±3% PSA 103 A˚ 2 Metabolism: demethylation, amide − . N log P 0 96 hydrolysis MeO

NH2

1/ O t 2 3h V 0.18 TRIMAZOSIN F 63% CL 1.0 Antihypertensive OMe N O pb – Mwt 435.5 Metabolism: hydroxylation of MeO N N ur – PSA 133 A˚ 2 gem-dimethyl to 1/ . ± . N OH log P 1.13 1-hydroxytrimazosin (t 2 1 6 0 5h) MeO

NH2

1/ O t 2 2–12 h V 0.72 BUNAZOSIN α N F 45% CL 4.8 1-Adrenergic antagonist MeO N N pb 94–97% Mwt 373.5 Metabolism: N-glucuronidation, ˚ 2 N ur 1% PSA 93.8 A O-demethylation, then MeO log P 2.27 O-glucuronidation NH2

1/ O t 2 10.5 h V – PAZINACLONE F –CL–Sedative, anxiolytic O pb 95% Mwt 478.9 Metabolism: acetal hydrolysis, then O N ur 0% PSA 84.9 A˚ 2 reduction of ketone to alcohol 1/ . log P 0.52 (t 2 7 6h)

Cl N N N O

t1/ 2h V –SURICLONE N 2 F –CL–Anxiolytic O N pb – Mwt 478.0 S Metabolism: oxidation to N-oxide, O ur – PSA 129 A˚ 2 S-oxide, N-demethylation S log P 3.81 Cl N N N O 427

t1/ 4±2h V 1.4–1.6 ZOPICLONE N 2 F 80% CL 3.6 Sedative, hypnotic O N pb 45% Mwt 388.8 Metabolism: N-demethylation, N ur 5% PSA 91.8 A˚ 2 N-oxidation of tertiary amine, O N log P 2.71 hydrolysis of carbamate N N O Cl

1/ ∗ OH t 2 1.4 h V 0.8 UK-240455 O O F 17% CL 6.0 ∗iv S pb 87% Mwt 368.2 NMDA glycine site antagonist, N H ur 58–68%∗ PSA 124 A˚ 2 crosses bbb Cl N O log P −1.11 Metabolism: glucuronidation

Cl N O H

61 Nucleoside Analogs

Chemically modiﬁed nucleosides can disrupt the biosynthesis of RNA and DNA by inhibiting essential enzymes, by blocking the elongation of nucleic acids, or by rendering the resulting RNAs/DNAs nonfunctional. Nucleoside analogs (‘‘antimetabolites’’) can thus be used to interfere with the replication of cells (e.g., as antineoplastics) and viruses [1] (Tables 61.1 and 61.2). Many of these compounds are mutagenic. Because of their low lipophilicity, the oral bioavailability of unnatural carbohydrates depends on the availability of suitable active transport mechanisms and can vary strongly.

Reference

1. (a) De Clercq, E. (2010) Highlights in the discovery of antiviral drugs: a personal retrospective. J. Med. Chem., 53, 1438–1450; (b) Parker, W.B. (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem. Rev., 109, 2880–2893.

Table 61.1 Nucleoside analogs with monocyclic heteroarenes. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ N O t 2 Short V – ACADESINE F <5% CL 37 Cardioprotectant HO N pb 1% Mwt 258.2 Metabolites: uric acid, O NH2 ur – PSA 157 A˚ 2 hypoxanthine NH2 OH log P −2.29 HO

t1/ 3h V 0.8 MIZORIBINE N O 2 F 12–81% CL 2.2–4.8 Immunosuppressant HO N pb – Mwt 259.2 Metabolism: phosphorylation O NH2 2 OH ur 50–100% PSA 151 A˚ OH log P −0.79 HO

1/ ∗ H t 2 0.1–0.5 h V – PYRAZOFURIN O ∗ N N F –CL–iv pb – Mwt 259.2 Antiviral HO O NH2 ur <12% PSA 162 A˚ 2 OH log P −1.75 OH HO

1/ O t 2 6–8 h (iv) V 1.1 TIAZOFURIN S F –CL2.4Antineoplastic, crosses bbb HO pb – Mwt 260.3 Metabolism: phosphorylation O N NH2 ur 50–85% (iv) PSA 154 A˚ 2 OH log P −0.78 HO

t1/ 2h∗ V 14 RIBAVIRIN N O 2 F 45–65% CL 5.2 ∗terminal phase: 18–36 h HO N pb 0% Mwt 244.2 Antiviral O N NH2 ur 35±8% PSA 144 A˚ 2 Metabolism: phosphorylation, OH log P −1.85 aminal and amide hydrolysis HO

1/ ∗ N NH t 2 28–76 h V 19 VIRAMIDINE F 66% CL 2.7 ∗monkey HO N pb 7% Mwt 243.2 Prodrug of ribavirin (see above) O N NH2 ur 1–4% PSA 151 A˚ 2 Metabolism: hydrolysis of aminal OH log P −1.72 to free triazole and amidine to HO amide and CO2H

t1/ 3.5 h (iv)∗ V 0.7∗ LEVOVIRIN N O 2 F 10% CL 2.6∗ ∗monkey HO N pb – Mwt 244.2 Antiviral (hepatitis C) O N NH2 ur 21%∗ PSA 144 A˚ 2 OH log P −2.26 HO

1/ ∗ ∗ O N t 2 1–2 h (iv) V 0.4–0.7 ZEBULARINE ∗ ∗ F <1% CL 4–11 ∗monkey HO O N pb 57% Mwt 228.2 DNA methylation inhibitor, ur – PSA 103 A˚ 2 antineoplastic − . OH log P 0 83 HO

(continued overleaf ) 430 61 Nucleoside Analogs

t1/ 1–4 h (sc) V 1.2±0.4 AZACYTIDINE O N NH2 2 F 18% CL 43±13 Antineoplastic for sc HO O N N pb – Mwt 244.2 administration ur – PSA 141 A˚ 2 Metabolism: phosphorylation − . OH log P 2 19 HO

t1/ 1–2 h (iv) V – DIHYDROAZACYTIDINE O N NH2 2 F –CL–Antineoplastic HO O N NH pb – Mwt 246.2 ur <20% (iv) PSA 141 A˚ 2 − . OH log P 2 20 HO

1/ . ∗ t 2 4h V 0 6 FAZARABINE, O N NH2 F –CL18ARABINOSYL-5-AZACYTIDINE ∗ HO O N N pb – Mwt 244.2 monkey ur – PSA 141 A˚ 2 Antineoplastic, iv administration − . OH log P 2 19 Metabolism: phosphorylation HO

t1/ 0.6 h (iv) V 0.2–4.6 DECITABINE O N NH2 2 F Low CL 130 Antineoplastic, crosses bbb; HO O N N pb 0% Mwt 228.2 Metabolism: deamination, ur – PSA 121 A˚ 2 phosphorylation log P −1.87 HO

1/ t 2 2–3 h V 0.49 CIDOFOVIR O N NH ∗ 2 F <5% CL 2.5 iv N pb 0–6% Mwt 279.2 Antiviral ur 80–100%∗ PSA 155 A˚ 2 Metabolism: phosphorylation; HO OH log P −1.47 prodrug: CMX001 O P O OH (hexadecyloxypropyl phosphonate; 1/ t 2 1 h (monkey))

1/ ± . ± . t 2 2 1h V 0 53 0 13 ZALCITABINE O N NH2 F 88±17% CL 4.1±1.2 Antiviral < HO O N pb 4% Mwt 211.2 Metabolism: phosphorylation ur 65±17% PSA 88.2 A˚ 2 log P −1.36

1/ ± . ± . t 2 11 2h V 1 0 0 7 TROXACITABINE, BCH-4556 O N NH2 F Low CL 2.5±1.0 Antineoplastic HO O N pb – Mwt 213.2 Metabolism: phosphorylation ur 60% (iv) PSA 97.4 A˚ 2 O log P −0.78 431

1/ t 2 5–7 h V 1.3 LAMIVUDINE O N NH2 F 86±16% CL 4.8 Antiviral HO O N pb 16–36% Mwt 229.3 Metabolite: trans-sulfoxide ur 55–85% PSA 113 A˚ 2 S log P −0.71

1/ t 2 3–5 h V 1 APRICITABINE O N NH2 F 65–80% CL – Nucleoside reverse transcriptase < HO S N pb 4% Mwt 229.3 inhibitor, antiviral (HIV) ur 65–80% PSA 113 A˚ 2 Metabolite: triphosphate O log P −1.35

1/ . ± . t 2 7–18 h V 1 4 0 3 EMTRICITABINE O N NH2 F 75–93% CL 4.7±1.5 Antiviral N pb <4% Mwt 247.3 Metabolite: 3-sulfoxide HO O F ur 75% PSA 113 A˚ 2 S log P −0.41

t1/ 1.3 h (iv) V – FIACITABINE O N NH2 2 F High CL – Antiviral N pb – Mwt 371.1 Metabolism: replacement of NH HO O I 2 ur 12% (iv) PSA 108 A˚ 2 by OH (to ﬁaluridine) − . F log P 1 54 HO

t1/ 0.2–0.4 h V 0.22–0.74 GEMCITABINE O N NH2 2 F 10% CL 17–54 Antineoplastic HO O N pb 0% Mwt 263.2 Metabolites: triphosphate and < ˚ 2 1/ ur 10% PSA 108 A diﬂuorodeoxyuridine (t 2 89 h) F log P −2.22 HO F

t1/ 2–6 h V 1.0–1.5 2-DEOXY-2- O N NH2 2 F 10–80% CL 4.1–6.2 METHYLENECYTIDINE, HO O N pb – Mwt 239.2 DMDC ur 30–50% PSA 108 A˚ 2 Antineoplastic log P −1.12 Metabolites: triphosphate and HO deoxymethyleneuridine

1/ ± ∗ . ∗ t 2 11 3h V 1 4 3 -C-ETHINYLCYTIDINE, TAS-106 O N NH2 F –CL1.7±0.2∗ ∗iv HO O N pb Low Mwt 267.2 Antineoplastic ur 62–71%∗ PSA 129 A˚ 2 − . OH log P 2 57 OH

(continued overleaf ) 432 61 Nucleoside Analogs

1/ . ± . . ± . t 2 2 6 0 6h V 3 0 1 9 CYTARABINE O N NH2 F 20% CL 13±4 Antineoplastic HO O N pb 13% Mwt 243.2 Metabolism: phosphorylation to ur 11±8% PSA 129 A˚ 2 triphosphate; 80–100% of the latter − . OH log P 1 81 is excreted in urine HO

1/ H t 2 5.3 h (iv) V 0.32 ENOCITABINE O N N ()20 F –CL0.9Antineoplastic pb – Mwt 565.8 HO O N O ur – PSA 132 A˚ 2 log P 8.62 OH HO

1/ H t 2 1–3 h V – SAPACITABINE O N N ()14 F –CL–Prodrug of CNDAC pb – Mwt 490.6 Values: CNDAC on oral HO O N O ur – PSA 135 A˚ 2 administration of prodrug log P 5.67 CN HO

1/ H t 2 0.5–0.9 h V – CAPECITABINE O N N O F 100% CL 64 Prodrug of 5-ﬂuorouracil pb 54% Mwt 359.4 N O O F ur 3% PSA 121 A˚ 2 log P 0.97 OH HO

1/ . ± . . ± . H t 2 1 1 0 2h V 1 4 0 4 ZIDOVUDINE O N O F 63±13% CL 26±6 Antiviral pb <25% Mwt 281.3 Metabolism: glucuronidation, N HO O ur 18±5% PSA 134.1 A˚ 2 intracellular phosphorylation, − . log P 0 09 reduction of azide to NH2, causes granulocytopenia and anemia N3

1/ H t 2 4–5 h V – ALOVUDINE O N O F High CL – Antiviral pb <10% Mwt 244.2 N HO O ur – PSA 78.9 A˚ 2 log P −0.20

F 433

1/ / t 2 20–100 h V F 23–40 ELVUCITABINE O N NH2 F 41% CL/F 6–12 Antiviral (HIV) N < HO O F pb 1% Mwt 227.2 Metabolism: phosphorylation ur 32% PSA 88.2 A˚ 2 log P −1.28

1/ t 2 1.3 h V 0.7–1.0 STAVUDINE H ± O N O F 86 18% CL 8.2 Antiviral pb 0% Mwt 224.2 Metabolism: hydroxylation, HO O N ur 34±5% PSA 78.9 A˚ 2 glucuronidation, epoxidation log P −0.65 followed by reaction with nucleophiles

1/ ± H t 2 40–49 h V 8 4 TELBIVUDINE O N O F 52% CL 3 Antiviral pb 3% Mwt 242.2 No metabolites N HO O ur 42% PSA 99.1 A˚ 2 log P −0.84 HO

1/ H t 2 4h V –FIALURIDINE O N O F –CL–Antiviral; discontinued because of pb – Mwt 372.1 excessive toxicity N HO O I ur – PSA 99.1 A˚ 2 log P 0.12 F HO

1/ H t 2 0.5 h (iv) V – IDOXURIDINE O N O F –CL–Antiviral pb – Mwt 354.1 Metabolites: idoxuracil, uracil N HO O I ur PSA 99.1 A˚ 2 –logP −0.59 HO

H t1/ 18 min (iv) V – TRIFLURIDINE, O N O 2 F –CL–TRIFLUOROTHYMIDINE N pb – Mwt 296.2 Antiviral; topical application only; HO O CF ˚ 2 3 ur – PSA 99.1 A too mutagenic for systemic − . log P 0 02 application HO Metabolite: 5-carboxyuracil

1/ H t 2 16 h V 1.2 BRIVUDINE O N O F 30% CL 3.7 Antiviral pb >95% Mwt 333.1 N Inactive metabolites: HO O < ˚ 2 Br ur 1% PSA 99.1 A bromovinyluracil, uracilacetic acid log P 0.29 HO (continued overleaf ) 434 61 Nucleoside Analogs

1/ H t 2 5–7 h V – SORIVUDINE O N O F 50–70% CL – Antiviral pb 98% Mwt 349.1 Metabolism: hydrolysis of aminal N HO O Br ur 74% PSA 119 A˚ 2 log P −0.03 OH HO

1/ H t 2 4–11 h V –TEGAFUR O N O F High CL – Antineoplastic pb 52% Mwt 200.2 Metabolism: hydrolysis of acetal to N O F ur 20% PSA 58.6 A˚ 2 5-ﬂuorouracil log P −0.60

t1/ 11±4min V 0.25±0.12 5-FLUOROURACIL H 2 O N O F 28% CL 16±7 Antineoplastic, metabolite of pb 10±2% Mwt 130.1 ﬂucytosine HN < ˚ 2 F ur 5% PSA 58.2 A Metabolite: 5,6-dihydro log P −0.65

1/ . ± . t 2 4 2 0 3h V 0.7–0.8 FLUCYTOSINE O N NH2 F 84±6% CL – Antifungal pb 4% Mwt 129.1 Metabolites: 6-hydroxy, HN F ur >90% PSA 67.5 A˚ 2 glucuronide, α-ﬂuoro-β-alanine log P −1.40

t1/ 1.1 h V – CARMOFUR H 2 O N O F CL Prodrug of 5-ﬂuorouracil H pb Mwt 257.3 N N ur PSA 78.5 A˚ 2 F log P 2.54 O

1/ O O t 2 2.5 h V – ACESULFAME S F 100% CL – Artiﬁcial sweetener ONH pb – Mwt 163.2 ur >99% PSA 80.8 A˚ 2 O log P −0.88

1/ S t 2 1–2 h V 0.3–0.4 PROPYLTHIOURACIL F 75% CL 3.9 Antihyperthyroid, anabolic HN NH pb 80% Mwt 170.2 Metabolism: glucuronidation, ur <10% PSA 73.2 A˚ 2 sulfation, S-methylation O log P 1.15 435

1/ O t 2 1h V –OROTICACID F <10% CL – Uricosuric HN NH pb 0% Mwt 156.1 ur – PSA 95.5 A˚ 2 HO2C O log P −0.84

1/ O t 2 2–5 h V 0.4–0.8 URAPIDIL F 63–80% CL 1.8–3.8 α1-Adrenergic antagonist, NN pb 75–80% Mwt 387.5 antihypertensive ˚ 2 1/ N N O ur 10–15% PSA 68.4 A Metabolites: 4-hydroxyaryl (t 2 H 1/ N log P 1.64 6–10 h), N-desmethyl (t 2 10–16 h)

OMe

t1/ 1.0–1.5 h V 0.14 NIFEKALANT O2N 2 OH O F –CL–Potassium channel blocker, NN pb – Mwt 405.5 antiarrhythmic N ur 30% PSA 122 A˚ 2 Metabolism: glucuronidation N O H log P 2.48

1/ ± . ± . t 2 21 9h V 4 6 1 2 ALOGLIPTIN ∗ F 72–88% CL 2.7±0.7 ∗monkey NC O pb – Mwt 339.4 DPPIV inhibitor, antidiabetic ur 60–71% PSA 93.7 A˚ 2 NN Metabolites: N-desmethyl, N-acetyl log P 1.84 H N 2 N O

1/ t 2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; bbb, blood–brain barrier; CNDAC, 1-(2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl)cytosine; DPPIV, dipeptidylpeptidase IV.

Table 61.2 Nucleoside analogs with bicyclic heteroarenes. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ . ± . . ± . N O t 2 1 4 0 3h V 1 0 0 2 DIDANOSINE F 38±15% CL 16±7 Antiviral N HO O NH pb <5% Mwt 236.2 Metabolite: hypoxanthine N ur 36±9% PSA 83.8 A˚ 2 log P −1.33

1/ ± N O t 2 15 2h V – INOSINE F –CL–Natural nucleoside N HO O NH pb – Mwt 268.2 N ur – PSA 129 A˚ 2 OH log P −1.97 HO

(continued overleaf ) 436 61 Nucleoside Analogs

1/ < t 2 2min(iv) V – ADENOSINE N NH2 F –CL–Natural nucleoside N HO O N pb 0% Mwt 267.2 N ur <5% PSA 140 A˚ 2 OH log P −0.76 HO

1/ O t 2 2h V – ISATORIBINE S O F Low CL – Immunomodulator, antiviral N HO O NH pb – Mwt 316.3 (hepatitis) N ur – PSA 183 A˚ 2 − . OH NH2 log P 2 17 HO

1/ t 2 1.4 h V 0.42 S-ADENOSYL-L-METHIONINE N NH2 F –CL3.4Natural electrophilic methylating H N S N 2 O N pb 5% Mwt 399.5 agent N ur 34–40% PSA 182.6 A˚ 2 HO2C OH HO log P −5.02

1/ t 2 1h V – VIDARABINE N NH2 F –CL–Antiviral, crosses bbb, active N HO O N pb 24–38% Mwt 267.2 metabolite: desamino (arabinosyl N ˚ 2 1/ . ur – PSA 140 A hypoxanthine, t 2 3 5h) OH log P −0.76 HO

t1/ 10–34 h∗ V 0.3–2.7 FLUDARABINE N NH 2 2 F 55–75% CL 1.1–6.3 ∗iv; antineoplastic; prodrug: N HO O N pb 19–29% Mwt 285.2 ﬂudarabine phosphate (F 55–75%, N ur 27–60% PSA 140 A˚ 2 ﬂudarabine on oral administration OH F log P −0.80 of prodrug) HO Metabolism: O-phosphorylation

1/ t 2 6–16 h V 1.3–9.2 CLADRIBINE N NH2 F 37–51% CL 11–22 ∗iv N HO O N pb 15–21% Mwt 285.7 Antineoplastic, crosses bbb ∗ N ur 30–50% PSA 119 A˚ 2 Metabolite: 2-chloroadenine Cl log P −0.98 HO

1/ ∗ t 2 5h V 4.5 CLOFARABINE ∗ ∗∗ F Low∗∗ CL 1.6 iv; rat: 50% N NH2 pb 47% Mwt 303.7 Antineoplastic N ∗ HO O N ur 49–60% PSA 119 A˚ 2 Metabolism: O-glucuronidation, N log P 0.45 O-sulfation, O-phosphorylation, F Cl aminal hydrolysis, replacement of HO NH2 by OH, oxidation of CH2OH to CO2H 437

1/ ∗ t 2 2h V 1.3 REGADENOSON N NH2 F –CL10∗iv HO N O N pb – Mwt 390.4 Adenosine A2A agonist, vasodilator N ur 19–77%∗ PSA 177 A˚ 2 OH N log P −3.09 HO H N N

1/ H t 2 12–20 h V 1–2 FORODESINE N O F 40–50% CL 1–2 Antineoplastic H pb – Mwt 266.3 HO N NH ur 40–70% (iv) PSA 130 A˚ 2 N log P −3.82 OH HO

1/ N O t 2 1.3 h V –2-DEOXYGUANOSINE F –CL–Natural nucleoside N HO O NH pb – Mwt 267.2 N ur – PSA 135 A˚ 2 log P −2.01 NH2 HO

t1/ 4.3±1.6h V 1.1±0.3 GANCICLOVIR N O 2 F 3% CL 4.6±1.8 Antiviral N HO O NH pb 1–2% Mwt 255.2 Metabolism: phosphorylation N ur 73±31% PSA 135 A˚ 2 log P −1.61 NH2 HO

1/ . ± . . ± . t 2 2 4 0 7h V 0 7 0 2 ACYCLOVIR F 15±5% CL 3.4 Antiviral; prodrug: ester with valine N O pb 15±4% Mwt 225.2 (valacyclovir); F (acyclovir on oral N ur 75±10% PSA 110 A˚ 2 administration of valacyclovir) 54% HO O NH N log P −1.76 Metabolism: 2-hydroxylation of imidazole, oxidation to NH2 (carboxymethoxymethyl) guanine, phosphorylation

1/ ∗ N O t 2 128–149 h V 1 ENTECAVIR F 70% CL 9 ∗monkey N HO NH pb 13% Mwt 277.3 Antiviral 2 N ur 75% PSA 121 A˚ 1/ Metabolites: phosphoryl (t 2 15 h), log P −0.96 NH2 glucuronide HO

(continued overleaf ) 438 61 Nucleoside Analogs

1/ N O t 2 10 h V – LOBUCAVIR F 30–40% CL 11 Antiviral HO N NH pb Low Mwt 265.3 N ur – PSA 121 A˚ 2 HO log P −1.24 NH2

t1/ 5–10 h (iv) V 0.6 PENTOSTATIN N OH 2 F Low CL 2.8 Antineoplastic HO O N pb 4% Mwt 268.3 Crosses bbb 2 N NH ur 96% (iv) PSA 112 A˚ log P −2.24 HO

1/ . ± . H t 2 1 5 0 6h V 0.84 ABACAVIR N N F 83% CL 13 Antiviral pb 50% Mwt 286.3 Metabolism: glucuronidation, HO N N ur 1.2% PSA 97.0 A˚ 2 oxidation of alcohol to carboxylic N log P 0.72 acid NH2

t1/ 0.5 h (iv) V 4.9 NELARABINE N OMe 2 F <10% CL 81 Prodrug for N HO O N pb 20% Mwt 297.3 arabinofuranosylguanine 2 1/ N ur – PSA 149 A˚ (t 2 2–6 h) log P −0.26 Metabolism: O-demethylation OH NH2 HO

1/ H t 2 0.5 h V – TECADENOSON N N O F –CL–Adenosine A1 agonist, pb – Mwt 337.3 antiarrhythmic HO O N N ur – PSA 135 A˚ 2 N log P −1.38 OH HO

1/ H t 2 2.5 h V – SELODENOSON, DTI-0009 N N F –CL–Adenosine A1 agonist pb – Mwt 376.4 O O N N ˚ 2 N ur – PSA 134 A NH OH log P 2.29 HO 439

t1/ 8±2h V 1.3 TICAGRELOR, AZD6140 HO H 2 N N N F Low CL – Platelet aggregation inhibitor, N pb <99.7% Mwt 522.6 antithrombotic N ur >0.05% PSA 164 A˚ 2 O N Metabolism: log P 2.02 O-de(hydroxyethylation), OH S N-decyclopropylation HO F F

1/ H t 2 2–5 h V –PELDESINE N N O F 33–59% CL 7.4 Nucleoside phosphorylase pb <14% Mwt 241.3 inhibitor, immunomodulator NH ur 82% PSA 96.2 A˚ 2 N log P −0.74 NH2

1/ t 2 0.5–4.0 h V 0.15 THIOGUANINE S F 14–46% CL 9–15 Antineoplastic H N pb – Mwt 167.2 Metabolism: S-methylation, N 2 ur Low PSA 111 A˚ replacement of NH2 by OH, N − . N NH2 log P 0 54 C-hydroxylation of imidazole, H conversion to thioguanosine-5-phosphate

1/ O t 2 17–29 h V 0.6–1.1 OXYPURINOL F – CL 0.3–0.5 Active metabolite of allopurinol NH pb <5% Mwt 136.1 HN ur – PSA 70.1 A˚ 2 N N O H log P 0.55

1/ OH t 2 1–2 h V 1.6 ALLOPURINOL F 67–90% CL 6–12 Xanthine oxidase inhibitor, N pb 3% Mwt 136.1 antiurolithic N ur <10% PSA 70.1 A˚ 2 Active metabolite: oxypurinol (see N N H log P −0.55 above)

1/ . ± . . ± . SH t 2 0 9 0 4h V 0 56 0 38 MERCAPTOPURINE F 12±7% CL 11±4 Antineoplastic, N N pb 19% Mwt 152.2 immunosuppressant; metabolized ur 22±12% PSA 85.2 A˚ 2 intracellularly to 6-thioinosinate N N H log P −0.30

1/ . ± . . ± . O2N N t 2 0 2 0 1h V 0 8 0 7 AZATHIOPRINE F 60±30% CL 57±31 Prodrug of 6-mercaptopurine, S N pb 30% Mwt 277.3 immunosuppressant ur <2% PSA 138 A˚ 2 Metabolites: mercaptopurine, N N log P −1.05 6-thiouracil, N N 6-methylmercaptopurine H

(continued overleaf ) 440 61 Nucleoside Analogs

t1/ 1.6–2.4 h V 0.8±0.4 TRAPIDIL N 2 F 100% CL – Vasodilator N N pb – Mwt 205.3 Metabolite: N-desethyl ˚ 2 1/ ur 2% PSA 46.3 A (t 2 4–5 h) N log P 2.31

1/ t 2 19 h V – IBUDILAST N N F –CL–Antiallergic, antiasthmatic, pb >95% Mwt 230.3 vasodilator, crosses bbb < . ˚ 2 O ur 0 1% PSA 34.4 A Metabolite: 6,7-dihydro log P 2.44

1/ O t 2 6–10 h V 0.6 THEOBROMINE F 80% CL 1.0 Antiasthmatic N NH pb 21% Mwt 180.2 Metabolism: N-demethylation, ur 10% PSA 67.2 A˚ 2 hydroxylation of imidazole (to N N O log P −1.06 methylated uric acids)

1/ ± . ± . O t 2 9 2h V 0 50 0 16 THEOPHYLLINE H F 96±8% CL 0.6±0.2 Antiasthmatic N N pb 56±4% Mwt 180.2 Metabolism: N-demethylation, ur 18±3% PSA 69.3 A˚ 2 hydroxylation of imidazole (to N N O log P −0.28 methylated uric acids)

t1/ 5±2h V 0.61±0.02 CAFFEINE O 2 F 100% CL 1.4±0.5 CNS stimulant, smoking doubles N N pb 36±7% Mwt 194.2 clearance ur 1.1±0.5% PSA 58.4 A˚ 2 Metabolism: N-demethylation, N N O log P −0.63 oxidation to uric acid, imidazole ring opening

1/ O t 2 1–2 h V 0.5–0.6 ENPROFYLLINE H F >85% CL 3–4 Bronchodilator N NH pb 47% Mwt 194.2 ur 85–91% PSA 78.1 A˚ 2 N N O log P 0.31

1/ O t 2 4h V 0.6 ETOFYLLINE HO F 80% CL 1.8 Vasodilator N N pb – Mwt 224.2 Metabolism: hydroxylation ur 16% PSA 78.7 A˚ 2 N N O log P −0.91 441

1/ t 2 8–12 h V 0.53–0.72 PROXYPHYLLINE O F 100% CL 0.78 Bronchodilator, vasodilator HO pb – Mwt 238.2 Metabolism: N3-demethylation N N ur 18–29% PSA 78.7 A˚ 2 N N O log P −0.56

1/ HO t 2 1.8–2.3 h V 0.4–0.8 DYPHYLLINE, DIPROPHYLLINE F 68–82% CL 4.8 Bronchodilator O < HO pb 3% Mwt 254.2 2 N N ur 85–88% PSA 98.9 A˚ log P −1.25 N N O

1/ ± O t 2 7 1h V 1 DOXOFYLLINE O F 63% CL – Bronchodilator O pb 48% Mwt 266.3 Metabolite: N N ur <4% PSA 76.9 A˚ 2 (hydroxyethyl)theophylline log P −0.87 N N O

1/ ± O t 2 48 11 h V – FURAFYLLINE H F –CL–Antiasthmatic N N pb – Mwt 260.3 ur PSA 82.4 A˚ 2 N N O log P 0.85

t1/ 0.9±0.3h V 4.2±0.9 PENTOXIFYLLINE O O 2 F 33±13% CL 60±13 Hemorheologic agent N N pb 0% Mwt 278.3 Metabolism: reduction of ketone to ur 0% PSA 75.5 A˚ 2 alcohol, oxidation to 4-carboxybutyl N N O log P −0.15 and 3-carboxypropyl-3,7- dimethylxanthine

1/ O O t 2 0.74 h V – PROPENTOPHYLLINE F 4%∗ CL – ∗rabbit N N pb – Mwt 306.4 Vasodilator ur – PSA 75.5 A˚ 2 Metabolism: reduction of ketone to N N O log P 0.87 alcohol

t1/ 1–2 h V 0.5 ACEFYLLINE HO2C O 2 F 1–2% CL 7 Diuretic, cardiotonic, N N pb – Mwt 238.2 bronchodilator ur – PSA 95.7 A˚ 2 N N O log P −0.78

(continued overleaf ) 442 61 Nucleoside Analogs

1/ / O t 2 47 h V F 3 ISTRADEFYLLINE, KW-6002 F –CL/F 1.5 Adenosine A2A antagonist for MeO N N pb – Mwt 384.4 treatment of Parkinson’s disease ur – PSA 76.9 A˚ 2 MeO N N O log P 2.63

1/ O t 2 14–25 h V 5.6 BG 9928 CO H ∗ 2 H F 92% CL – ∗monkey N N pb – Mwt 416.5 Adenosine A1 antagonist, ur – PSA 107 A˚ 2 natriuresis enhancer N N O log P 3.79

1/ ∗ t 2 1.6 h V – ETAMIPHYLLINE N F 84%∗ CL – ∗rat O pb – Mwt 279.3 Bronchodilator ur 20%∗ PSA 61.7 A˚ 2 N N log P 0.57 N N O

1/ t 2 1–2 h V 18 BAMIFYLLINE HO N F –CL–Bronchodilator; active metabolite: O 1/ pb – Mwt 385.5 des(hydroxyethyl) (t 2 18 h) ur – PSA 81.9 A˚ 2 N N log P 1.08 N N O

1/ ± t 2 16 8h V – TAZIFYLLINE N N F –CL–Histamine H1 antagonist pb – Mwt 472.6 S O ˚ 2 HO ur – PSA 110 A N N log P 1.91

N N O

1/ O t 2 3–5 h V 1.5 SILDENAFIL F 41% CL 9.1 Phosphodiesterase V inhibitor N NH O O pb 96% Mwt 474.6 Metabolism: N-demethylation, N S ur <2% PSA 113 A˚ 2 oxidative degradation of piperazine N N log P 2.28 N O 443

1/ O t 2 4–5 h V 3 VARDENAFIL F 15% CL 13 Active metabolite: N-desethyl NH O O pb 95% Mwt 488.6 N N S ur 2–6% PSA 118 A˚ 2 N N log P 3.03 N O

1/ O t 2 7–12 h V – UDENAFIL, DA-8159 ∗ F 38–56% CL/F 7–23 ∗rat N NH O O pb 94% Mwt 516.7 Phosphodiesterase V inhibitor N S ur – PSA 121 A˚ 2 Metabolism: hydroxylation, N N H log P 3.08 N-demethylation, N-dealkylation of O N sulfonamide

1/ t 2 113–130 h V 4–40 LINAGLIPTIN F 15–51%∗ CL 0.2–1.1 ∗rat O pb 75–99% Mwt 472.5 DPPIV inhibitor, antidiabetic H2N ˚ 2 N ur 2.4% PSA 113 A Metabolism: hydroxylation of N N N log P 1.99 propargylic CH3, oxidation of N N N O aromatic CH3 to CO2H, acetylation of NH2, oxidative deamination to piperidin-3-one, then reduction to alcohol

t1/ 2.3±0.4h V 0.98±0.13 FAMCICLOVIR O 2 ± . ± . N F 77 8% CL 8 0 1 5 Antiviral O N pb <20% Mwt 321.3 Prodrug of penciclovir (diol, F 5%); O N ur 74±9% PSA 122 A˚ 2 all data: diol on oral dosing of N NH2 log P −0.12 diacetate O

t1/ 5–11 h∗∗ V 0.42∗ ADEFOVIR DIPIVOXIL O 2 F 60%∗ CL 3.7∗ Prodrug of adefovir (phosphonic NH ∗ O 2 pb 4% Mwt 501.5 acid); O O ∗ 2 ∗ N ur 45% PSA 172 A˚ adefovir on oral dosing of prodrug N ∗∗ O O log P 2.45 prodrug: 1.6 h (iv) P N O O N

1/ t 2 4–14 h V – PRADEFOVIR ∗ ∗ Cl NH2 F 19% CL – monkey pb – Mwt 423.8 Prodrug of adefovir (phosphonic N N ur – PSA 124 A˚ 2 acid) O O P N N log P 1.67 O O

(continued overleaf ) 444 61 Nucleoside Analogs

1/ ∗ . ∗∗ t 2 12–26 h V 0 83 TENOFOVIR DISOPROXIL O ∗ ∗ OiPr OiPr F 25% CL 3.8 ∗tenofovir on oral dosing of ∗ NH2 < O O O pb 1% Mwt 519.4 prodrug ∗∗ ˚ 2 ∗∗ N N ur 70–80% PSA 190 A tenofovir iv O O log P 2.04 Antiviral, prodrug of tenofovir P N O O N (phosphonic acid)

1/ t 2 1–2 h V – ERYTHROHYDROXYNONYL- NH2 F –CL–ADENINE (EHNA) N N pb – Mwt 277.4 Adenosine deaminase inhibitor ur – PSA 89.9 A˚ 2 N HO N log P 2.61

1/ O t 2 1.3 h (iv) V 0.17 KRN-5500 F –CL2.7 O Antineoplastic N OH pb – Mwt 589.7 H HN OH ur – PSA 209 A˚ 2 log P 1.60 HO O NH H HO N N

N N H

t1/ <1h V – ROSCOVITINE HN 2 F –CL–CDK inhibitor; crosses bbb N N pb 90% Mwt 354.5 Metabolism: oxidation of alcohol to ur <3% (rat) PSA 87.9 A˚ 2 carboxyl, N-dealkylation N N NH log P 1.68 OH

t1/ 10±4h V – V-11294A HN 2 F –CL–PDE4-inhibitor N N pb – Mwt 409.5 Metabolite: N-desethyl ur 1% PSA 74.1 A˚ 2 (t1/ 10±2h) N 2 N log P 4.84 O

OMe 445

1/ O t 2 1.7–1.9 h V – BOF-4272 F –CL–Xanthine oxidase inhibitor for N N NH pb – Mwt 366.4 treatment of hyperuricemia ur 1% PSA 89.4 A˚ 2 Metabolism: hydroxylation, N log P 2.62 reduction to sulﬁde, oxidation to sulfone MeO

Ph S O

1/ t 2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchanged drug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surface area; CDK, cyclin-dependent kinases; CNS, central nervous system; PDE, phosphodiesterase. 446

62 Dihydropyridines

Dihydropyridines are readily prepared from ammonia, acetoacetic esters, and aldehydes (Scheme 62.1). This one-step synthesis does not allow any structural modiﬁcation of the 1,4-dihydropyridine substructure but only a limited variation of the substituents.

RO C CO R RO2C CO2R 2 2 H O + 3 H2O

O O N H NH3

Scheme 62.1 Synthesis of dihydropyridines.

Dihydropyridines, discovered 1967 by Friedrich Bossert and Wulf Vater at Bayer, are one of the three main types of calcium channel blockers known (the other two are verapamil and diltiazem) and mainly act as vasodilators. Their target indications are angina and hypertension (Table 62.1). Dihydropyridines such as nifedipine mainly undergo dehydrogenation to pyridines and ester hydrolysis in vivo. Some drugs of this type, though, have long half-lives, because the alkoxycarbonyl groups are in fact vinylogous carbamates, that is, the lone electron pair at the amino group stabilizes the ester against nucleophilic attack.

Table 62.1 Dihydropyridines (calcium channel blockers, antihypertensives). V inlkg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ . ± . . ± . t 2 2 5 1 3h V 0 8 0 2 NIFEDIPINE F 50±13% CL 7±2 NO2 pb 96±1% Mwt 346.3 2 MeO2C CO2Me ur <1% PSA 110 A˚ log P 3.58 N H

1/ t 2 7–15 h V 2–7 NISOLDIPINE F 4–8% CL 8–16 O NO2 pb 99% Mwt 388.4 CO Me ur 0% PSA 110 A˚ 2 O 2 log P 4.38 N H

t1/ 4±2h V 3.8±1.3 NITRENDIPINE NO2 2 F 14–55% CL 21±4 CYP3A4 substrate O pb 98% Mwt 360.4 ur <1% PSA 110 A˚ 2 CO2Me O log P 3.81 N H

t1/ 11±2h V 24 NILVADIPINE NO2 2 F 14–19% CL 7–18 O pb 98% Mwt 385.4 ur 0% PSA 134 A˚ 2 CO2Me O log P 3.38 N CN H

t1/ 1–3 h V 1.7±0.6 NIMODIPINE NO2 2 F 10±4% CL 19±6 CYP3A substrate MeO O O pb 98% Mwt 418.4 ur <1% PSA 120 A˚ 2 O O log P 4.05 N H

1/ ± ± Cl t 2 14 4h V 10 3 FELODIPINE F 15±8% CL 12±5 CYP3A substrate O Cl pb 99% Mwt 384.3 Metabolism: aromatization, < . ˚ 2 CO2Me ur 0 5% PSA 64.6 A ester hydrolysis, hydroxylation O log P 4.76 of methyl groups N H

(continued overleaf ) 448 62 Dihydropyridines

1/ N t 2 2–4 h V – DARODIPINE O F –CL28 N pb 97% Mwt 371.4 2 EtO2C CO2Et ur – PSA 104 A˚ log P 3.88 N H

1/ ± ± N t 2 8 5h V 4 2 ISRADIPINE O F 19±7% CL 10±1 O N pb 97% Mwt 371.4 ˚ 2 CO2Me ur 0% PSA 104 A O log P 3.73 N H

1/ t 2 2–3 h V – CILNIDIPINE, CINALDIPINE NO2 Ph F –CL– MeO O O pb – Mwt 492.5 ur – PSA 120 A˚ 2 O O log P 5.36 N H

1/ t 2 2–11 h V 0.9–2.3 LACIDIPINE F 2–52% CL 125 > CO2tBu pb 95% Mwt 455.5 ˚ 2 EtO2C CO2Et ur 0% PSA 90.9 A log P 5.99 N H

1/ < Cl t 2 10 min V 0.6 CLEVIDIPINE F – CL 142–170 Antihypertensive for iv dosing > Cl O O pb 99% Mwt 456.3 ur 0% PSA 90.9 A˚ 2 MeO2C O O log P 5.46 N H

1/ t 2 3–11 h V 2.0–2.5 LERCANIDIPINE NO2 F 3–40% CL 336 CYP3A4 substrate O pb >98% Mwt 611.7 ur 0% PSA 114 A˚ 2 MeO2C O log P 7.56 N N H Ph

Ph 62 Dihydropyridines 449

1/ t 2 4–8 h V – MANIDIPINE NO2 F –CL– pb 99% Mwt 610.7 O ur 0% PSA 117 A˚ 2 MeO C 2 O log P 5.66 N N H N

Ph Ph

1/ . ± . . ± . t 2 1 3 0 5h V 1 1 0 3 NICARDIPINE NO2 F 18±11% CL 10.4±3.1 pb 98–99% Mwt 479.5 O ur <1% PSA 114 A˚ 2 MeO C 2 O log P 4.89 N N H Ph

1/ ∗ O t 2 10–24 h V – ELGODIPINE ∗ F –CL– iv O O pb – Mwt 524.6 iPrO C F 2 2 O ur – PSA 86.3 A˚ N log P 6.20 N H

1/ t 2 8–20 h V – BARNIDIPINE NO2 F 3–4% CL 9–10 CYP3A4 substrate Ph pb 92–99% Mwt 491.5 Metabolism: ester hydrolysis, O N ur 0% PSA 114 A˚ 2 oxidation to pyridine, and MeO C 2 O log P 5.13 N-debenzylation

N H

1/ ± ± t 2 39 8h V 16 4 AMLODIPINE F 74±17% CL 5.9±1.5 Metabolism: deamination Cl pb 93±1% Mwt 408.9 ur 5–10% PSA 99.9 A˚ 2 MeO2C CO2Et log P 4.16 O N NH2 H

63 Arenesulfonamides

The sulfonamide group may be either a replaceable structural element of drugs or an essential pharmacophore. Sulfonamides show exceptional chemical and metabolic stability and do not undergo hydrolysis in vivo. The half-life of these drugs mainly depends on their rate of renal excretion and metabolic degradation of other functional groups. Mainly three types of drug owe their biological activity to a sulfonamide group: antibacterial 4-aminobenzenesulfonamides (inhibitors of folate biosynthesis by mimicking 4-aminobenzoic acid), hypoglycemic sulfonylureas (blockers of the ATP-sensitive potassium channel), and diuretics (carbonic anhydrase inhibitors) (Table 63.1).

63.1 Antibacterials

Prontosil, a prodrug of sulfanilamide, was patented in 1932 by the German chemists Josef Klarer and Fritz Mietzsch (I.G. Farben). The credit for the discovery of prontosils antibacterial properties went to Gerhard Domagk, a research director at I.G. Farben, who was awarded the 1938 Noble Prize in Medicine for his discovery. Prontosil was a true breakthrough in the treatment of bacterial infections, and numerous other improved sulfonamide antibacterials were developed later. As mimetics of 4-aminobenzoic acid, these compounds inhibit the bacterial biosynthesis of folate. The widespread use of these sulfonamides at high doses revealed some interesting side effects, which led to the development of the sulfonamide-based diuretics and the hypoglycemic sulfonylureas (Chapter 64).

63.2 Diuretics

Diuretics are used to treat several diseases, not all of them being directly related to renal function [1]. The adjustment of volume or composition of body ﬂuids can be required for the treatment of heart failure, hypertension, cirrhosis, nephrotic syndrome, and renal failure.

The ﬁrst diuretics used as such were plant extracts containing digitoxin, caffeine, or theobromine. In 1886, Ernst Jendrassik´ reported that Hg2Cl2 (calomel) had a strong diuretic effect. Extracts of digitalis to which small amounts of mercurous chloride had been added were used as diuretics until the 1950s. Two physicians, Alfred Vogl and Paul Saxl, at the First Medical University of Vienna discovered the diuretic properties of organomercurials. These were originally used only as antiseptics or to treat syphilis, but careful monitoring of the patients clearly revealed their potent diuretic effect. Compounds such as merbaphen, mersalyl, mercamphamide, mercaptomerin, and chlormerodrin were common diuretics until the 1950s (Scheme 63.1).

O OMe

CO2Na N CO2Na O Hg N O O N O O O O NH H O Cl Hg Cl OMe N CO H NN H 2 Mercumatilin HgOH O Merbaphen Mersalyl t1/2 3.3 h

O O O NaO C 2 OMe HO2C OMe OMe N N H2N N H H H Hg HgOH HgCl Mercaptomerin Mercamphamide Chlormerodrin S CO2Na t1/2 12 min

Scheme 63.1 Organomercurials as drugs.

Organomercurials act by binding to thiol groups in dehydrogenases located in renal tubules, thereby inhibiting these enzymes. Because of the (surprisingly low) toxicity of these organomercurials, other less toxic diuretics were sought. One of these was the Michael acceptor ethacrynic acid, launched in 1962, also an irreversible dehydrogenase inhibitor. High doses of sulfonamide antibacterials, such as sulfanilamide (4-amino- benzenesulfonamide), also induce diuresis. In 1940, it was discovered that many sulfonamides with unsubstituted nitrogen (RSO2NH2) inhibit carbonic anhydrase, the enzyme that catalyzes the addition of water to CO2. Because the kidneys contain large amounts of carbonic anhydrase, it was correctly proposed in 1941 that the diuretic effect of sulfonamides was due to inhibition of renal carbonic anhydrase. The search for more potent and selective sulfonamide-based carbonic anhydrase inhibitors led to the discovery of a large number of useful diuretics, the ﬁrst being acetazolamide (1952) and chlorothiazide (1957).

Reference

1. Sneader, W. (1997) Diuretics. Drug News Perspect., 10, 364–369. 452 63 Arenesulfonamides

Table 63.1 Sulfonamides and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

t1/ 48±12 h V 0.21±0.02 DIAZOXIDE O O 2 F 86–96% CL 0.06±0.02 Antihypoglycemic, Cl S NH pb 94±14% Mwt 230.7 antihypertensive 2 ur 35±15% PSA 66.9 A˚ Metabolism: hydroxylation of CH3, N log P 1.19 then oxidation to CO2H

t1/ 1.5±0.2h V 0.20±0.08 CHLOROTHIAZIDE O O O O 2 F 33–56% CL 4.5±1.7 Diuretic, antihypertensive S S ± H2N NH pb 95 1% Mwt 295.7 ur 92±5% PSA 135 A˚ 2 Cl N log P −0.15

1/ . ± . O O O O t 2 7–15 h V 0 8 0 3 HYDROCHLOROTHIAZIDE ± . ± . S S F 71 15% CL 4 9 1 1 Diuretic H2N NH pb 58±17% Mwt 297.7 Metabolism: hydrolysis of aminal ur >95% PSA 135 A˚ 2 Cl N (4% in urine) H log P −0.02

1/ ± O O O O t 2 10 7h V 5 HYDROFLUMETHIAZIDE ± S S F 63 12% CL 6.4 Diuretic, antihypertensive H2N NH pb 74% Mwt 331.3 Metabolism: hydrolysis of aminal ur 50–70% PSA 135 A˚ 2 F3C N H log P 0.08

1/ O O O t 2 6–15 h V – QUINETHAZONE F –CL– S Diuretic, antihypertensive H2N NH pb – Mwt 289.7 ur – PSA 110 A˚ 2 Cl N H log P 3.59

1/ . ± . O O O O t 2 3 8 1 2h V 1.0–1.5 BENDROFLUMETHIAZIDE S S F 60–90% CL 4.3 Diuretic, antihypertensive H2N NH pb 94% Mwt 421.4 Ph ur 30% PSA 135 A˚ 2 F3C N H log P 1.29

1/ O O O O t 2 5–15 h V – BENZTHIAZIDE S S F 60–70% CL – Diuretic, antihypertensive H2N NH pb 30% Mwt 431.9 S Ph ur <1% PSA 161 A˚ 2 Cl N log P 2.58 453

1/ O O O O t 2 26 h V 4.1 POLYTHIAZIDE S S F High CL – Diuretic, antihypertensive H2N N pb 80–85% Mwt 439.9 S CF ˚ 2 Cl N 3 ur 25% PSA 152 A H log P 2.05

1/ . ± . . ∗ O O O O t 2 2 3 1 9h V 0 4 TRICHLORMETHIAZIDE S S F 60% CL 3.4 ∗calves H N NH 2 pb – Mwt 380.7 Diuretic, antihypertensive Cl ˚ 2 Cl N ur 62–70% PSA 135 A H log P 0.13 Cl

1/ O O O t 2 17 h V 10.6 FENQUIZONE > S F 53% CL – Diuretic H2N NH pb – Mwt 337.8 ur – PSA 110 A˚ 2 Cl N H log P 4.17

t1/ 14±8h V 1.6 METOLAZONE O O O 2 F 40–65% CL 1.4 S Diuretic, antihypertensive H2N N pb 95% Mwt 365.8 ur 80–95% PSA 101 A˚ 2 Cl N H log P 3.16

t1/ 10 h V – TRIPAMIDE H 2 F >80% CL – Diuretic, antihypertensive O O O pb – Mwt 369.9 Metabolism: hydrazide hydrolysis, S N < 2 H2N N H ur 1.5% PSA 101 A˚ hydrazide N-acetylation, H log P 2.21 hydroxylation of bicycyloalkyl group Cl

t1/ 9±3h V 1.5 CLOPAMIDE O 2 O O F 85% CL 2.5 Antihypertensive, diuretic S N pb 46% Mwt 345.8 H2N N H ur 33% PSA 101 A˚ 2 Cl log P 2.08

1/ ± t 2 18 6h V 0.4–1.6 INDAPAMIDE O O O F 93% CL – Antihypertensive, diuretic S N pb 79% Mwt 365.8 Metabolism: indoline H2N N 2 H ur 5–7% PSA 101 A˚ 5-hydroxylation, dehydrogenation Cl log P 1.96 to indole, then oxidation to indol-3-one (continued overleaf ) 454 63 Arenesulfonamides

t1/ 8±5h V 4.8–8.0 MEFRUSIDE O O O 2 F >70% CL 5.8–33 Diuretic S O γ H2N N pb 64% Mwt 382.9 Metabolism: oxidation to -lactone, ur 0.5% PSA 124 A˚ 2 then hydrolysis to hydroxy Cl log P 1.79 carboxylic acid

t1/ 7±1h V 0.3 XIPAMIDE O 2 O O F 73% CL 0.54 Diuretic, antihypertensive S pb 99% Mwt 354.8 Metabolism: O-glucuronidation H2N N H ur 40% PSA 118 A˚ 2 Cl OH log P 2.19

1/ ± . ± . O t 2 47 22 h V 0 10 0 04 CHLORTHALIDONE F 64±10% CL 0.04±0.01 Diuretic, antihypertensive O O HN pb 75±1% Mwt 338.8 Metabolism: reversible ring S ur 65±9% PSA 118 A˚ 2 H N opening to benzophenone 2 OH log P 0.70 Cl

1/ O O O O t 2 – V – DICHLORPHENAMIDE S S F –CL–Carbonic anhydrase inhibitor for H2N NH2 pb 55% Mwt 305.2 treatment of glaucoma ˚ 2 Cl ur – PSA 137 A Duration of action: 6–12 h log P 0.34 Cl

1/ N t 2 2–3 h V 0.26 AZOSEMIDE O O HN N F 15–20% CL 1.7 Diuretic S N pb >95% Mwt 370.8 H2N Metabolism: N-dealkylation ur 27% PSA 163 A˚ 2 S Cl N log P 1.40 H

1/ . ± . O O t 2 0.3–3.4 h V 0 11 0 02 FUROSEMIDE F 61±17% CL 2.0±0.4 S CO2H Diuretic H2N pb 98.8±0.2% Mwt 330.7 Metabolism: acyl glucuronidation, ± ˚ 2 Cl N O ur 66 7% PSA 131 A N-dealkylation H log P 2.30

1/ . ± . . ± . O O t 2 0 8 0 2h V 0 13 0 03 BUMETANIDE S CO H F 59–89% CL 2.6±0.5 Diuretic H N 2 2 pb 99% Mwt 364.4 Metabolism: glucuronidation, β-, ± ˚ 2 γ δ O ur 62 20% PSA 127 A -, and -hydroxylation of butyl, log P 2.88 N-debutylation, oxidation of CH to HN 3 CO2H 455

1/ . ± . O O t 2 1 0 0 5h V 0.25–0.30 PIRETANIDE S CO H F 80% CL 3.8±0.8(iv) Diuretic H N 2 2 pb 94% Mwt 362.4 Metabolism: cleavage of pyrrolidine ˚ 2 O ur 50% PSA 118 A to aminobutanol log P 2.30 N

1/ t 2 2–5 h V 0.16–0.39 NIMESULIDE F 50–70% CL 0.5–1.8 Antiinﬂammatory, hepatotoxic H Main metabolite: 4-hydroxyphenoxy S N pb 96–99% Mwt 308.3 O 2 1/ ± ur 1–3% PSA 110 A˚ (t 2 6 3h) O log P 2.70 Further metabolism: reduction of O NO 2 NO2 to NH2, then oxidation to quinoneimine, followed by reaction with nucleophiles

1/ ∗ H t 2 5h (iv) V – FLOSULIDE ∗ O S N F 63% CL – ∗monkey O pb – Mwt 353.3 COX-2 inhibitor F O ur – PSA 80.8 A˚ 2 O log P 2.05 F

1/ O O t 2 11–16 h V 5.7–7.1 CELECOXIB S F 40% CL 6–8 Antiinﬂammatory, analgesic H2N pb >97% Mwt 381.4 Metabolism (by CYP2C9): < ˚ 2 N N ur 2% PSA 81.4 A hydroxylation of CH3, then CF3 log P 4.21 oxidation to CO2Hand glucuronidation

1/ O O t 2 17–26 h V – CIMICOXIB, UR-8880 ∗ ∗ S F 45% CL – dog H2N pb 90% Mwt 381.8 COX-2 inhibitor, antiinﬂammatory, < ˚ 2 antidepressant N ur 0.2% PSA 90.7 A N log P 2.11 Metabolism: O-demethylation, then F glucuronidation Cl MeO

(continued overleaf ) 456 63 Arenesulfonamides

1/ ± t 2 9 2h V 1.3 VALDECOXIB Antiinﬂammatory, analgesic O O F 83% CL 1.7 Metabolism: glucuronidation, S pb 98% Mwt 314.4 H2N ur <5% PSA 94.6 A˚ 2 reductive cleavage of N–O bond, log P 1.71 4-hydroxylation of Ph, O hydroxylation of CH3, then N oxidation to CO2H; withdrawn in 2005 for adverse skin reactions and increasing risk of myocardial infarction

1/ O O O t 2 0.3–1.0 h V – PARECOXIB S F –CL–Water soluble, injectable prodrug N pb – Mwt 370.4 of valdecoxib H ur – PSA 97.7 A˚ 2 Metabolism: N-depropionylation O log P 1.72 N

1/ > O O t 2 200 h V – DuP 697 S F –CL–COX-2 inhibitor pb – Mwt 411.3 Long half-life due to enterohepatic ur – PSA 70.8 A˚ 2 recirculation; development Br log P 4.24 discontinued S

1/ t 2 17 h V 1.4 ROFECOXIB O O F 93% CL 1.9 Antiinﬂammatory, analgesic S pb 87% Mwt 314.4 Metabolism: 4-hydroxylation and ur <1% PSA 68.8 A˚ 2 3,4-dihydroxylation of Ph, log P 1.34 hydrogenation of oleﬁn, O hydroxylation at CH2O, reversible lactone hydrolysis; withdrawn in O 2004 because of risk of thrombosis and myocardial infarction

1/ O O t 2 21–27 h V 1.6–1.7 ETORICOXIB S F 100% CL 0.7–0.8 Antiinﬂammatory, analgesic pb 92% Mwt 358.8 Metabolism: hydroxylation of CH3, 2 Cl ur <1% PSA 68.3 A˚ then oxidation to CO2Hand log P 2.21 glucuronidation N

N 457

1/ t 2 16–20 h V – SULFLURAMID F F F F F F F F O O F –CL–Insecticide S F N pb – Mwt 527.2 Metabolism: N-deethylation F F F F F F F F H ur – PSA 54.6 A˚ 2 log P 7.79

1/ . ± . t 2 4 0 1 5h V – ETHOXZOLAMIDE O F 65% CL – N O Carbonic anhydrase inhibitor, S pb >95% Mwt 258.3 diuretic, antiglaucoma agent 2 O S NH2 ur 40% PSA 119 A˚ log P 2.14

t1/ 133 d V –DORZOLAMIDE NH 2 F –CL–Carbonic anhydrase inhibitor; O O pb 33% Mwt 324.4 antiglaucoma agent S ur 30–40% PSA 151 A˚ 2 Metabolism (CYP2E1 and S NH S 2 log P 0.10 CYP3A2): N-deethylation O O

1/ NH t 2 111 d V – BRINZOLAMIDE F –CL–Carbonic anhydrase inhibitor; O O pb 60% Mwt 383.5 antiglaucoma agent S N ur High PSA 164 A˚ 2 Metabolism: N-deethylation, S NH S 2 log P 0.28 O-demethylation, O O OMe N-demethoxypropylation

t1/ 7±5h V 0.2–0.4 ACETAZOLAMIDE O 2 H O F 100% CL 0.65 Carbonic anhydrase inhibitor, N S S NH pb 85–95% Mwt 222.3 antiglaucoma agent, diuretic 2 ˚ 2 O NN ur 100% PSA 152 A log P −0.26

1/ t 2 14 h V 0.07 METHAZOLAMIDE O O F 100% CL 0.01 Carbonic anhydrase inhibitor; N S S pb 72% Mwt 236.3 diuretic NH2 ur 25–60% PSA 139 A˚ 2 Metabolism: conjugation with O NN log P 0.13 cysteine (by nucleophilic displacement of SO2NH2 by thiol)

1/ ± t 2 59 9h V 1.2–1.8 ZONISAMIDE F 38–40% CL 0.26–0.32 Antiepileptic O N O O pb 50–60% Mwt 212.2 Metabolism: N-acetylation and S ur 15–35% PSA 94.6 A˚ 2 N-hydroxylation of sulfonamide, NH2 log P 0.72 hydroxylation of CH2, reductive N–O bond cleavage, then reduction of imine to amine and N-acetylation

(continued overleaf ) 458 63 Arenesulfonamides

1/ ± O O t 2 9 3h V –SULTHIAME S F >90% CL – Anticonvulsant, carbonic anhydrase O O NH2 pb 29% Mwt 290.4 inhibitor S ˚ 2 N ur 17–69% PSA 114 A Metabolism: hydroxylation log P 0.56

1/ . ± . t 2 4–12 h V 0 17 0 03 PROBENECID O O F 100% CL 0.4 Uricosuric S ± N pb 90 5% Mwt 285.4 Metabolism: acyl glucuronidation, 2 ur 1.2±0.2% PSA 83.1 A˚ hydroxylation at CH2CH3 and CH3, HO2C log P 2.51 N-depropylation, oxidation of CH3 to CO2H

t1/ 1.0–1.3 h V – ACETOHEXAMIDE O O 2 F –CL–Antidiabetic S N pb 90% Mwt 324.4 Active metabolite: alcohol H 2 1/ . ± . ur Low PSA 101 A˚ (t 2 6 5 1 5 h) formed by reduction log P 2.44 of the acetyl group O

1/ / t 2 7–13 h V F 1 SITAXENTAN F 70–100% CL/F 1.3–1.5 Endothelin antagonist, treatment of O N O O O pb >99% Mwt 454.9 pulmonary hypertension; crosses S < ˚ 2 bbb N ur 1% PSA 144 A S H Cl log P 2.77 Metabolism: benzylic O hydroxylation, then oxidation to O 1,2-diketone, hydrolysis of acetal, then O-methylation

1/ . ± . . ± . t 2 9 9 4 3h V 0 29 0 04 SULFADIAZINE O O N F 100% CL 0.55±0.17 Antibacterial S ± N N pb 54 4% Mwt 250.3 Metabolism: aniline N-acetylation H ur 57±14% PSA 106 A˚ 2 and N-hydroxylation, pyrimidine − . H2N log P 0 07 4-hydroxylation

1/ ± t 2 4 2h V –GLYMIDINE O O O N OMe F –CL–Antidiabetic S pb 80–90% Mwt 309.3 Metabolism: O-demethylation N N ˚ 2 H ur 1% PSA 98.8 A log P −0.07 459

t1/ 100–230 h V 0.37–0.41 SULFADOXINE N N 2 O O F High CL – Antibacterial S N OMe pb 90% Mwt 310.33 Metabolism: N-acetylation H ˚ 2 OMe ur 30–60% PSA 125 A H2N log P 0.46

1/ ± . ± . O t 2 10 5h V 0 21 0 02 SULFAMETHOXAZOLE O O N F 100% CL 0.32±0.04 Antibacterial S ± N pb 62 5% Mwt 253.3 Metabolism: aniline N-acetylation H ur 14±2% PSA 107 A˚ 2 and N-hydroxylation, H2N log P 0.66 N-glucuronidation of sulfonamide

t1/ 6.6±0.7h V 0.15±0.02 SULFISOXAZOLE O N 2 O O F 96±14% CL 0.33±0.01 Antibacterial S ± N pb 91 1% Mwt 267.3 Metabolism: aniline N-acetylation H ur 49±8% PSA 107 A˚ 2 H2N log P 1.01

1/ t 2 4–11 h V 0.1 SULFAMOXOLE F –CL–Antibacterial O O N pb 25% Mwt 267.3 S Metabolism: N-acetylation N O ur 65–71% PSA 107 A˚ 2 H log P 0.68 H2N

1/ ± t 2 9 4h V 0.4–1.2 SULFAPYRIDINE O O F 20% CL 0.6–2.1 Metabolite of sulfasalazine; all S N N pb 50% Mwt 249.3 values: sulfapyridine on oral dosing H ur 10–20 % PSA 93.5 A˚ 2 of sulfasalazine H2N log P 0.47 Metabolism: N-acetylation

1/ Cl t 2 23.5 h V 0.11 TENIDAP F 89% CL 0.06 Antiinﬂammatory pb >99% Mwt 320.8 Metabolism: benzene and ur <1% PSA 112 A˚ 2 thiophene hydroxylation; log P 1.59 hepatotoxic S N NH2 OH O O

1/ ± O O t 2 68 8h V 0.12–0.15 TENOXICAM S F 100% CL 0.02–0.06 Antiinﬂammatory N H pb >99% Mwt 337.4 Metabolism: pyridine S N N ur Negligible PSA 136 A˚ 2 5 -hydroxylation, thiophene log P 0.01 2-hydroxylation, glucuronidation OH O

(continued overleaf ) 460 63 Arenesulfonamides

1/ ± t 2 4 1h V 0.1–0.2 LORNOXICAM O O F 100% CL 0.36–0.81 Antiinﬂammatory, analgesic; S . N pb 99.7% Mwt 371.8 pyridyl: pKa 5 5 Cl H ur Negligible PSA 136 A˚ 2 Metabolism: pyridine N N S log P 0.77 5 -hydroxylation, glucuronidation; OH O 5 -hydroxylornoxicam does not undergo enterohepatic recirculation

1/ ± / . ± . t 2 48 8h V F 0 15 0 03 PIROXICAM O O F 100% CL/F 0.04 Antiinﬂammatory S N pb 99% Mwt 331.4 Metabolism: pyridine H < 2 N N ur 5% PSA 108 A˚ 5 -hydroxylation, then log P 0.59 glucuronidation, hydrolysis of OH O amide, then decarboxylation, cyclodehydration

1/ t 2 22–45 h V 0.2 ISOXICAM O O F 97% CL 0.08 Antiinﬂammatory, does not cross S N pb 98% Mwt 335.3 bbb H 2 N ur 2% PSA 121 A˚ Metabolism: hydroxylation of log P 0.90 CCH3, withdrawn in 1985 because OH O N O of fatal skin reactions

1/ O O t 2 24–96 h V 0.2–0.3 SUDOXICAM S F High CL – Antiinﬂammatory, hepatotoxic due N H pb – Mwt 337.4 to hydrolysis and N-dealkylation to N S ur – PSA 136 A˚ 2 acylthiourea and reactive aldehyde; log P 2.36 development stopped in phase III OH O N

1/ ± O O t 2 19 5h V 0.14–0.21 MELOXICAM S F 89–97% CL 0.10–0.16 Nonhepatotoxic, antiinﬂammatory N H pb >99% Mwt 351.4 Metabolism (by CYP2C9): N 2 S ur <0.3% PSA 136 A˚ hydroxylation of CCH3, then log P 2.66 oxidation to thiazole carboxylic acid OH O N

1/ O O t 2 21 h V – CP 14304 S F –CL–Metabolism: 4-hydroxylation of Ph N H pb – Mwt 330.4 N ur PSA 95.1 A˚ 2 log P 0.89 OH O 461

1/ t 2 26–42 h V 0.22 ROQUINIMEX N O F 100% CL 0.1 Antineoplastic pb – Mwt 308.3 Metabolism: hydroxylation, N ur 1% PSA 60.9 A˚ 2 N-demethylation, glucuronidation OH O log P 1.03

1/ t 2 80 h V 0.2 LAQUINIMOD N O F 82–95% CL – Treatment of multiple sclerosis pb 99% Mwt 356.8 Metabolism: N-deethylation, N ur 10% PSA 60.9 A˚ 2 N-demethylation, aniline and Cl OH O log P 2.69 quinolone aromatic hydroxylation

64 Sulfonylureas

The antidiabetic effect of sulfonylureas was discovered two times. In France, physicians noticed in 1942 that some sulfonamides used for the treatment of typhoid fever caused hypoglycemia in patients and experimental animals. Despite recognizing its importance, this ﬁnding remained unexploited during the war, as the lack of food also lowered the number of diabetics. In 1954, Hans Franke and Joachim Fuchs rediscovered the hypoglycemic properties of the sulfonylurea carbutamide by testing it on themselves. This compound was the ﬁrst sulfonylurea used to treat type II diabetes, but had to be withdrawn because of adverse effects on bone marrow. It was replaced by tolbutamide (1956), and since then a large number of sulfonylureas with improved potency and pharmacokinetics (PK) properties were developed (Table 64.1). As the potency of sulfonylureas increased, toxicity became less of an issue. Sulfonylureas block the ATP-sensitive potassium channel in pancreatic β-cells, and thereby stimulate the release of insulin. Hence, these drugs can only be used to treat type II diabetes, where the pancreas is still capable of producing insulin.

Table 64.1 Sulfonylureas. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

t1/ 30±6h V – CARBUTAMIDE O O O 2 S F –CL–Antidiabetic with high bone N N pb – Mwt 271.3 marrow toxicity H H ur – PSA 110 A˚ 2 Metabolism: N-acetylation H N 2 log P 1.01

t1/ 5.9±1.4h V 0.10±0.02 TOLBUTAMIDE O O O 2 F 93±10% CL 0.24±0.04 Antidiabetic; CYP2C9 substrate S N N pb 96±1% Mwt 270.4 Metabolism: benzylic H H ur 0% PSA 83.7 A˚ 2 hydroxylation, then oxidation to log P 2.36 benzoic acid

1/ ± / . ± . t 2 33 6h V F 0 1 0 01 CHLORPROPAMIDE O O O F >90% CL/F 0.03±0.005 Antidiabetic S pb 96±0.6% Mwt 276.7 Metabolism: propyl 2- and N N H H ur 20±18% PSA 83.7 A˚ 2 3-hydroxylation, N-depropylation, Cl log P 2.30 hydrolysis to 4-chlorobenzenesulfonamide

1/ ± t 2 8 3h V 0.25 GLIBORNURIDE F 91% CL – Antidiabetic O O O pb 95% Mwt 366.5 Metabolism: benzylic S N N ur – PSA 104 A˚ 2 hydroxylation, then oxidation to H H OH log P 2.69 benzoic acid

1/ ± t 2 14 6h V 0.18–0.34 GLICLAZIDE F 79–100% CL 0.19 Antidiabetic O O O pb 85–95% Mwt 323.4 Metabolism: glucuronidation, S N ur <1% PSA 86.9 A˚ 2 benzylic hydroxylation, then N N H H log P 1.61 oxidation to benzoic acid, methylene hydroxylation at cyclopentane

1/ ± t 2 6 2h V – TOLAZAMIDE F –CL–Antidiabetic O O O pb 94% Mwt 311.4 Metabolism: benzylic S N N N ur 4–8% PSA 86.9 A˚ 2 hydroxylation, then oxidation to H H log P 1.54 benzoic acid, 4-hydroxylation of azepine, hydrolysis to toluenesulfonamide

1/ ± t 2 4 1h V 0.19–0.23 TORSEMIDE, TORASEMIDE F 75–89% CL 0.5–0.6 Diuretic NH O O O pb >99% Mwt 348.4 Metabolism: benzylic hydroxylation S ur 20–25% PSA 109 A˚ 2 and oxidation to carboxylic acid, N N H H log P 1.96 hydroxylation of CHCH3, aromatic N 4-hydroxylation

1/ OMe t 2 0.6–0.7 h V – CLAMIKALANT F 86% CL 4–5 Potassium channel blocker, H H N N pb High Mwt 472.0 antiarrhythmic HN S ur – PSA 146 A˚ 2 Cl O O S O log P 1.54

MeO

(continued overleaf ) 464 64 Sulfonylureas

t1/ 17±3h V 0.2±0.1 GLYBURIDE, GLIBENCLAMIDE O O O 2 F 64–100% CL 1.3±0.5 Antidiabetic S N N pb 99.8% Mwt 494.0 Metabolism: 4-trans and 3-cis H H ur Negligible PSA 122 A˚ 2 hydroxylation of cyclohexyl HN log P 3.08 Cl O

MeO

1/ . ± . . ± . t 2 3 4 0 7h V 0 17 0 02 GLIPIZIDE O O O F 95% CL 0.52±0.18 Antidiabetic S N N pb 98% Mwt 445.5 Metabolism: cyclohexyl 3- and H H ur <5% PSA 139 A˚ 2 4-hydroxylation, hydroxylation of HN log P 1.88 CH3 N O N

1/ ± t 2 15 9h V – GLIQUIDONE O O O F –CL–Antidiabetic S N N pb – Mwt 527.6 Poorly water soluble H H ur Negligible PSA 130 A˚ 2 Metabolism: cyclohexyl O log P 3.91 4-hydroxylation OMe N

t1/ 6±3h V 0.12 GLIMEPIRIDE O O O 2 F 100% CL 0.6–0.8 Antidiabetic S N N pb 99.4% Mwt 490.6 Metabolism: hydroxylation of H H ˚ 2 HN ur 0% PSA 133 A cyclohexyl-bound CH3 (to 1/ . ± . log P 3.45 hydroxyglimepiride; t 2 3 1 0 4h) O N

1/ t 2 2h V 0.4 GLISOXEPID O O O F 95% CL 0.9 Antidiabetic S N N N pb 93% Mwt 449.5 H H ur – PSA 142 A˚ 2 HN log P 0.81 O N O 64 Sulfonylureas 465

1/ F t 2 11–12 h V –ELINOGREL HN F 50% CL – Antiplatelet agent

O pb – Mwt 524.0 Metabolism: N-demethylation ur – PSA 173 A˚ 2 HN N O O O log P 3.00 O S N N S H H Cl

65 Benzodiazepines

Benzodiazepines belong to the few types of drug that originated from a purely chemical approach, without seeking inspiration in natural products. During the mid-1950s, Leo Sternbach at Hoffmann-La Roche Inc., Nutley, was trying to ﬁnd a new type of tranquilizer and prepared a series of compounds related to his postdoctoral work [1]. Initially, these were believed to be heptoxdiazines, A,but turned out to be quinazoline-N-oxides, B (Scheme 65.1).

R′ O R′ N N R′ NH H+ not O but N N OH N O R ABR R

Scheme 65.1 Synthesis of quinazoline-N-oxides.

Because all the compounds tested were inactive, and other, more urgent work had to be done, the project was halted in the second half of 1955. Two years later, while cleaning up the laboratory, the crystalline product of the reaction of methylamine with quinazoline-N-oxide, C (Scheme 65.2) was found and submitted for direct testing in animals (something unthinkable today). This product turned out to be a potent tranquilizer of low toxicity and had good pharmacokinetic (PK) properties. Again, a wrong structure (D) had initially been assigned to this product, which turned out to be the benzodiazepine chlordiazepoxide (E). This compound was launched 1960 under the trademark Librium.

H N N N N Cl N H N CH3NH2 N Cl O notCl O but Cl N C D O E

Chlordiazepoxide (librium) t 1/2 10 h, F 100%

Scheme 65.2 Synthesis of chlordiazepoxide.

Since then thousands of benzodiazepines were prepared and evaluated, and many of them reached the market (Table 65.1). These compounds are mainly used as anxiolytics and hypnotics. The main metabolic pathways of representative benzodiazepines are sketched in Scheme 65.3. Often, the metabolites of benzodiazepines are biologically active, and the dosing must be adjusted accordingly. All benzodiazepines cross the blood–brain barrier (bbb).

H N NH2 H O N N N

demethylation hydrolysis Cl N Cl N Cl N O O O

Chlordiazepoxide N-Desmethylchlordiazepoxide Demoxepam − t 1/2 10 h, F 100% t 1/2 14 95 h

H O H O N N

reduction hydroxylation OH Cl N Cl N glucuronidation

Nordazepam Oxazepam t 1/2 73 h, F 99% t 1/2 8 h, F 97%

Scheme 65.3 Metabolism of benzodiazepines.

Reference

1. Sternbach, L.H. (1979) The benzodiazepine story. J. Med. Chem., 22, 1–7. 468 65 Benzodiazepines

Table 65.1 Benzodiazepines and related compounds. V inlkg−1,CLinmlmin−1 kg−1,and Mwt in g mol−1.

1/ O t 2 14–30 h V – NIMETAZEPAM N F 95% CL – Anticonvulsant, muscle relaxant; 3 pb – Mwt 295.3 Metabolism: hydroxylation (C-3), ur – PSA 78.5 A˚ 2 reduction of NO to NH , then O2N N 2 2 log P 2.31 Ph N-acetylation, and N-demethylation (slowest reaction)

1/ ± . ± . H O t 2 26 3h V 1 9 0 3 NITRAZEPAM N F 78±16% CL 0.86±0.12 Anticonvulsant, hypnotic; ± pb 87 1% Mwt 281.3 Metabolism: reduction of NO2 to ur <1% PSA 87.3 A˚ 2 NH , then N-acetylation O2N N 2 log P 2.1 Ph

1/ ± . ± . O t 2 15 5h V 3 3 0 6 FLUNITRAZEPAM N F 85% CL/F 3.5±0.4 Hypnotic pb 77–79% Mwt 313.3 Metabolism: reduction of NO2 to ur <1% PSA 78.5 A˚ 2 NH , N-demethylation, O2N N 2 log P 2.1 hydroxylation of CH2 F

1/ ± . ± . H O t 2 23 5h V 3 2 1 1 CLONAZEPAM N F 98±31% CL/F 1.55±0.28 Anticonvulsant pb 86±0.5% Mwt 315.7 Metabolism: reduction of NO2 to ur <1% PSA 87.3 A˚ 2 NH , then N-acetylation, O2N N 2 log P 2.8 hydroxylation of CH2 Cl

1/ ± . ± . O t 2 43 12 h V 1 1 0 3 DIAZEPAM (VALIUM) N F 100±14% CL 0.38±0.06 Anxiolytic, muscle relaxant pb 99% Mwt 284.8 Metabolism: N-demethylation, < ˚ 2 Cl N ur 1% PSA 32.7 A hydroxylation of CH2 group, then log P 2.7 glucuronidation Ph

1/ ± . ± . O t 2 15 4h V 6 7 2 1 TETRAZEPAM N F –CL–Muscle relaxant pb 70–90% Mwt 288.8 Metabolism: N-demethylation, ˚ 2 Cl N ur – PSA 32.7 A allylic hydroxylation, then log P 2.63 aromatization of cyclohexenyl to diazepam and nordazepam 469

1/ ± . ± . H O t 2 73 33 h V 0 78 0 12 NORDAZEPAM N F 99±6% CL 0.14±0.05 Anxiolytic pb 97.5% Mwt 270.7 Metabolite of diazepam < 2 Cl N ur 1% PSA 41.5 A˚ log P 2.9 Ph

1/ O t 2 23–48 h V – FLUDIAZEPAM N F –CL–Anxiolytic pb – Mwt 302.7 Metabolism: N-demethylation Cl N ur – PSA 32.7 A˚ 2 log P 2.9 F

1/ ± ± H O t 2 74 24 h V 22 7 N-DESALKYLFLURAZEPAM N F –CL/F 4.5±2.3 Main metabolite of flurazepam, pb 96.6% Mwt 288.7 fludiazepam, and flutoprazepam Cl N ur <1% PSA 41.5 A˚ 2 log P 2.60 F

1/ ± . ± . H O t 2 15 5h V 1 1 0 3 BROMAZEPAM N F 60% CL 0.7±0.1 Anxiolytic pb 70% Mwt 316.2 Metabolism: hydroxylation of CH2, ˚ 2 Br N ur 2.3% PSA 54.4 A then O-glucuronidation, amide and log P 2.4 imine hydrolysis, aromatic N hydroxylation

1/ . ± . . ± . t 2 1 3 0 7h V 14 4 5 1 PRAZEPAM ± O F –CL/F 140 100 Anxiolytic N pb – Mwt 324.8 Prodrug of nordazepam ur 0% PSA 32.7 A˚ 2 Cl N log P 3.6 Ph

1/ < t 2 6h V – FLUTOPRAZEPAM ± O F 85 5% CL – Anxiolytic N pb – Mwt 342.8 Metabolism: ur – PSA 32.7 A˚ 2 N-decyclopropylmethylation Cl N log P 3.7

(continued overleaf ) 470 65 Benzodiazepines

1/ t 2 1–5 h V 0.8–1.7 PINAZEPAM O F 40–50% CL 4–9 Anxiolytic N pb 94–97% Mwt 308.8 Metabolism: hydroxylation of 2 ur – PSA 32.7 A˚ CH2CO; in rat liver microsomes Cl N log P 2.9 depropargylation is eight times Ph faster than demethylation of diazepam

1/ ± F3C t 2 15 1h V 1 HALAZEPAM O F –CL6.2Anxiolytic N pb – Mwt 352.7 Metabolism: N-dealkylation to ur – PSA 32.7 A˚ 2 nordazepam Cl N log P 3.54 Ph

t1/ 14–36 h V 8.6 QUAZEPAM F3C 2 S F 29–35% CL 13.7 Sedative, hypnotic N pb >95% Mwt 386.8 Metabolites: N-desalkylﬂurazepam, 2 1/ ur – PSA 47.7 A˚ 2-oxoquazepam (t 2 40 h), and Cl N 1/ log P 4.03 N-desalkylquazepam (t 2 70–75 h) F

1/ ± . ∗ t 2 16 6h V 3 1 ESTAZOLAM ∗ N F 98%∗ CL 18∗ mice N Sedative, hypnotic N pb 93% Mwt 294.7 ur <5% PSA 43.1 A˚ 2 Metabolism: hydroxylation of log P 2.52 triazole and CH2, aromatic N Cl 4-hydroxylation, then Ph glucuronidation, hydrolysis of imine

1/ ± . ± . N t 2 13 2h V 0 72 0 12 ALPRAZOLAM N F 88±16% CL 0.74±0.14 Anxiolytic metabolism: N ± pb 71 3% Mwt 308.8 hydroxylation of CH3,andCH2, ur 20% PSA 43.1 A˚ 2 imine hydrolysis Cl N log P 2.3 Ph

1/ ± / . ± . N t 2 3 1h V F 1 1 0 4 TRIAZOLAM N F 44% CL/F 5.6±2.0 Sedative, hypnotic; CYP3A N pb 90±2% Mwt 343.2 substrate 2 ur 2% PSA 43.1 A˚ Metabolism: hydroxylation of CH3 Cl N log P 2.9 and CH2; withdrawn in 1991 in the United Kingdom Cl 471

1/ . ± . . ± N t 2 1 9 0 6h V 1 1 6 MIDAZOLAM F 44±17% CL 6.6±1.8 Anesthetic for iv dosing N ± pb 95 2% Mwt 325.8 Metabolism: hydroxylation of CH3 ± 2 ur 56 26% PSA 30.2 A˚ and CH2 Cl N log P 3.1

1/ . ± . . ± . N t 2 0 9 0 2h V 1 0 0 2 FLUMAZENIL ± CO2Et F 20% CL 17 3 Benzodiazepine antagonist N pb 42% Mwt 303.3 Metabolism: ester hydrolysis, then ur <1% PSA 64.4 A˚ 2 glucuronidation F N log P 2.15 O

t1/ 2h V 4 RO 48-8684 N N 2 F –CL28Sedative N O pb – Mwt 411.5 Metabolism: N-depropylation 2 N ur – PSA 62.5 A˚ F N log P 2.39 O

t1/ 0.5 h V 3 RO 48-6791 N N O 2 F –CL27Sedative N N pb – Mwt 412.5 Metabolism: N-depropylation 2 N ur – PSA 80.3 A˚ F N log P 2.53 O

1/ . ± . N t 2 2 9 0 3h V 1.6 ADINAZOLAM Me2N N F 33–45% CL 6.8 Antidepressant; Main metabolite: N 1/ pb 64–75% Mwt 351.8 N-desmethyl (t 2 2–8 h) ur <2% PSA 46.3 A˚ 2 Cl N log P 1.27 Ph

1/ ± t 2 3 2h V – MEDAZEPAM N F –CL–Anxiolytic pb >95% Mwt 270.8 Active metabolite: diazepam and 2 Cl N ur – PSA 15.6 A˚ N-desmethylmedazepam log P 3.4 (t1/ 40–80 h) Ph 2

(continued overleaf ) 472 65 Benzodiazepines

t1/ 11–23 h V – METACLAZEPAM OMe 2 N F –CL–Anxiolytic pb – Mwt 393.7 Metabolism: N- and 2 Br N ur – PSA 24.8 A˚ O-demethylation, aromatic log P 3.86 hydroxylation, imine hydrolysis Cl

t1/ 6–11 h V – CAMAZEPAM O O 2 N F >90% CL – Anxiolytic O N pb – Mwt 371.8 Metabolism: hydrolysis of 2 Cl N ur – PSA 62.2 A˚ carbamate, N-demethylation log P 2.6 Ph

1/ ± . ± . O t 2 11 6h V 0 95 0 34 TEMAZEPAM N F 91% CL 1.0±0.3 Sedative, hypnotic OH pb 97.6% Mwt 300.8 Metabolism: N-demethylation, < 2 Cl N ur 1% PSA 52.9 A˚ O-glucuronidation; withdrawn in log P 2.1 Ph 1999 in Sweden and Norway for risk of abuse

1/ . ± . . ± . H O t 2 8 0 2 4h V 0 6 0 2 OXAZEPAM N F 97±11% CL 1.05±0.36 Anxiolytic OH pb 99±2% Mwt 286.7 Metabolism: glucuronidation < 2 Cl N ur 1% PSA 61.7 A˚ log P 1.8 Ph

1/ . ± . / . ± . H O t 2 2 0 0 9h V F 0 33 0 17 CLORAZEPIC ACID N F 5% CL/F 1.8±0.2 Anxiolytic; prodrug of nordazepam

CO2H pb – Mwt 314.7 < 2 Cl N ur 1% PSA 78.8 A˚ log P 2.54 Ph

1/ O t 2 10 h V 4.6 LORMETAZEPAM N F 80% CL 4 Sedative, hypnotic OH pb 85% Mwt 335.2 Metabolism: O-glucuronidation, 2 Cl N ur – PSA 52.9 A˚ N-demethylation log P 2.7 Cl 473

1/ ± . ± . H O t 2 14 5h V 1 3 0 2 LORAZEPAM N F 93±10% CL 1.1±0.4 Anxiolytic OH pb 91±2% Mwt 321.2 Metabolism: glucuronidation Cl N ur <1% PSA 61.7 A˚ 2 log P 2.5 Cl

1/ ± O t 2 66 11 h V – CLOXAZOLAM N F –CL–Anxiolytic pb – Mwt 363.2 Prodrug of Cl N ur – PSA 32.8 A˚ 2 chlorodesmethyldiazepam Cl O log P 3.9 Metabolism: twofold N-dealkylation

1/ H O t 2 70 h V – MEXAZOLAM N F –CL–Anxiolytic pb – Mwt 363.2 Metabolism: N-dealkylation to Cl N ur – PSA 41.6 A˚ 2 chlorodesmethyldiazepam Cl O log P 4.4

1/ H O t 2 10–20 h V –OXAZOLAM N F –CL–Sedative, anxiolytic, anticonvulsant pb – Mwt 328.8 Metabolism: N-dealkylation to 2 Cl N ur – PSA 41.6 A˚ desmethyldiazepam O log P 3.8

1/ O t 2 2h V – KETAZOLAM N F –CL–Sedative, anxiolytic, anticonvulsant pb 93% Mwt 368.8 Active metabolite: N-desmethyl ˚ 2 1/ Cl N ur – PSA 49.9 A (t 2 52 h) Ph O O log P 0.51

t1/ 14–16 h V 9.8 CLENTIAZEM Me N O O 2 2 N F 35–50% CL 13.8 Antihypertensive O pb – Mwt 449.0 Metabolism: deacetylation, ur – PSA 84.4 A˚ 2 N-demethylation, O-demethylation, Cl S log P 4.46 aromatic hydroxylation (ortho to methoxy)

OMe

(continued overleaf ) 474 65 Benzodiazepines

1/ t 2 5–6 h V 3.1–1.2 DILTIAZEM Me N O O 2 N F 44±10% CL 12±4 Antianginal, antihypertensive, ± O pb 78 3% Mwt 414.5 antiarrhythmic ur 0.2–4.0% PSA 84.4 A˚ 2 Metabolites: desacetyl (t1/ 9±2h), S 2 1/ . ± . log P 4.73 N-monodesmethyl (t 2 7 5 1 0h)

OMe

1/ t 2 2h V 3.4 FLURAZEPAM Et N O 2 N F 83% CL 4.5±2.3 Sedative, hypnotic pb 75% Mwt 387.9 Metabolism: N-dealkylation to < 2 Cl N ur 1% PSA 35.9 A˚ 2-hydroxyethyl and log P 3.6 N-desalkylﬂurazepam, F hydroxylation of CH2 to doxefazepam

t1/ 9h V – CINOLAZEPAM NC O 2 N F –CL–Sedative, anxiolytic, anticonvulsant OH pb – Mwt 357.8 Metabolism: N-dealkylation, 2 Cl N ur – PSA 76.7 A˚ glucuronidation log P 1.7 F

t1/ 3–4 h V – DOXEFAZEPAM HO O 2 N F –CL–Sedative, anxiolytic OH pb – Mwt 348.8 Metabolism: glucuronidation, 2 Cl N ur – PSA 73.1 A˚ N-dealkylation, oxidation of log P 1.6 CH2OH to CO2H, and ring F contraction to quinazolinone

1/ ± . ± . H t 2 10 3h V 0 30 0 03 CHLORDIAZEPOXIDE N F 100% CL 0.54±0.49 Sedative, hypnotic N pb 97±2% Mwt 299.8 Metabolism: N-demethylation, ur <1% PSA 53.1 A˚ 2 hydrolysis of amidine to amide N Cl 1/ O log P 2.1 (demoxepam; t 2 14–95 h), hydrolysis and reduction to desmethyldiazepam

1/ ± O t 2 20 10 h V 0.9–1.5 CLOBAZAM N F 90% CL 0.35–0.65 Anxiolytic, anticonvulsant pb 85–90% Mwt 300.7 Metabolism: N-demethylation (to < 2 1/ Cl N ur 1% PSA 40.6 A˚ N-desmethyl, t 2 36–46 h), O log P 1.25 aromatic 4-hydroxylation 475

1/ . ± . H O t 2 7 9 1 2h V – PREMAZEPAM N F –CL–Anxiolytic, sedative N pb – Mwt 253.3 Metabolism: N-demethylation, ˚ 2 N ur 63% PSA 46.4 A hydroxylation of CH3 log P 1.31

1/ ± O t 2 13 5h V 3–4 CLOTIAZEPAM S N F 2.5% CL 9–10 Anxiolytic, sedative, hypnotic pb 99% Mwt 318.8 Metabolism: N-demethylation, N ur – PSA 60.9 A˚ 2 hydroxylation log P 3.95 Cl

1/ N t 2 3–15 h V –ETIZOLAM N F 87% CL – Anxiolytic, sedative, hypnotic S N pb 93% Mwt 342.9 Metabolism: hydroxylation of ethyl 2 ur <3% PSA 71.3 A˚ to 1-hydroxyethyl and of CH3, then N log P 2.20 glucuronidation

1/ ± N t 2 6 2h V 0.7 BROTIZOLAM N F 70±22% CL 1.7±0.4 Anxiolytic, sedative, hypnotic N S pb 90% Mwt 393.7 Metabolism: hydroxylation of CH3, < 2 Br ur 1% PSA 71.3 A˚ and CH2 N log P 2.46

1/ ± t 2 7 2h V – LOPRAZOLAM N N F –CL–Anxiolytic, sedative O pb – Mwt 464.9 Metabolism: formation of N ˚ 2 1/ N ur – PSA 97.3 A piperazine N-oxide (t 2 12–16 h), log P 0.60 reduction of NO2 to NH2

O2N N Cl

(continued overleaf ) 476 65 Benzodiazepines

1/ HN t 2 1.6 h (iv) V 0.84 BMS-214662 F –CL9.6Farnesyltransferase inhibitor, N pb – Mwt 489.6 antineoplastic N ur – PSA 130 A˚ 2 Metabolism: hydroxylation, log P 3.78 glucuronidation NC N S S O O

1/ O t 2 54–92 h V 4.2 COLCHICINE MeO F 37–44% CL 1.9 Gout suppressant N pb 32% Mwt 399.4 ˚ 2 MeO H ur 10–25% PSA 83.1 A log P 1.07 MeO O OMe

1/ t 2 2.7–3.5 h V 8–79 TOFISOPAM F –CL– MeO Anxiolytic N pb – Mwt 382.5 Metabolism: sequential ur – PSA 61.6 A˚ 2 O-demethylation MeO N log P 3.64

MeO MeO

1/ t 2 4–7 h V – TALAMPANEL O O F –CL6.7Anticonvulsant N pb 67–88% Mwt 337.4 Metabolism: N-acetylation, O N ur – PSA 77.2 A˚ 2 reductive cleavage of acetal to log P 1.30 7-O-methylcatechol, glucuronidation

H2N

66 Steroids

Natural steroids are endogenous hormones of short plasma half-life, low oral bioavailability, and usually, little therapeutic value [1] (Scheme 66.1). Although these lipophilic compounds are quickly and completely absorbed from the gastrointestinal (GI) tract, ﬁrst-pass metabolism is too extensive for oral dosing. Chemically modiﬁed steroids (agonists or antagonists), however, can show much improved pharmacokinetic properties (Table 66.1).

20 13 21 10 O 18 O OH 12 OH OH 11 O OH 1 H 16 H H H 2 H H 15 H H H H H H HO 7 O O O 4 6 Estradiol Testosterone Progesterone Cortisone (an estrogen, (an androgen, (a progestin, (a corticosteroid, induces feminization) induces virilization) maintenance of pregnancy) an antiinflammatory)

Scheme 66.1 Biological activities of steroids.

Estrogens and progestins are mainly used as contraceptives for the treatment of female infertility and in hormone replacement therapy, for example, for the treatment of menopausal symptoms. Androgens are used as anabolics or in hormone replacement therapy. The growth of hormone-responsive neoplasms can be suppressed by antiestrogens or antiandrogens. Corticosteroids (e.g., cortisone) are mainly used as systemic or topical antiinﬂammatories [2]. A number of nonsteroids may also interact with steroid receptors as agonists or antagonists. The main phase I metabolic transformations of steroids include the reduction/ oxidation of ketones/alcohols, aromatic and allylic hydroxylation, hydrogenation of alkenes (mainly enones), and hydrolysis of esters. Phase II conjugation reactions include glucuronidation and sulfation of hydroxyl groups.

References

1. Sneader, W. (2000) The discovery of oestrogenic hormones. J. Br. Menopause Soc., 129–133. 2. Khan, M.O.F. and Lee, H.J. (2008) Synthesis and pharmacology of anti-inﬂammatory steroidal antedrugs. Chem. Rev., 108, 5131–5145.

Table 66.1 Steroids. V is in l kg−1,CLinmlmin−1 kg−1 and Mwt in g mol−1.

1/ t 2 0.5 h (iv) V 0.29 BECLOMETHASONE O ∗ F 15–20% CL 36 DIPROPIONATE O O O pb 87% Mwt 521.0 Antiallergic, antiasthmatic, OH ur <10% PSA 107 A˚ 2 topical antiinﬂammatory O log P 4.07 Metabolism: ester H hydrolysis; ∗ 1/ . Cl H 17-monopropionate (t 2 2 7 O h) after oral administration of dipropionate

1/ O OH t 2 5.6 h (iv) V 1.3 BETAMETHASONE OH F 80% CL 2.8 Glucocorticoid HO pb 64% Mwt 392.5 Metabolism: H ur 5% PSA 94.8 A˚ 2 glucuronidation F H log P 2.03 O

1/ . ± . . ± . O OH t 2 3 0 0 8h V 0 8 0 2 DEXAMETHASONE OH F 78±14% CL 3.7±0.9 HO Antiinﬂammatory pb 68±3% Mwt 392.5 Metabolism: allylic H ur 8% PSA 94.8 A˚ 2 hydroxylation, reduction of F H log P 2.03 ketone to alcohol, O glucuronidation, sulfation

t1/ 1.4–3.6 h V 1.4–2.1 TRIAMCINOLONE O OH 2 OH F 23% CL 9–17 Glucocorticoid HO pb 71–79% Mwt 394.4 Metabolism: oxidation of H OH ur Low PSA 115 A˚ 2 11-alcohol to ketone, F H log P 0.53 hydrogenation of 4,5-alkene O

1/ . ± . O OH t 2 2.3–4.0 h V 1 7 0 3 METHYLPREDNISOLONE OH F 80% CL 6.1 Glucocorticoid, crosses bbb HO pb 77% Mwt 374.5 Metabolites: 20-β-hydroxy, H ur <10% PSA 94.8 A˚ 2 oxidation of 11-hydroxy to H H log P 2.17 ketone (methylprednisone) O 479

1/ . ± . . ± . O OH t 2 1 9 0 4h V 0 8 0 1CLOPREDNOL OH . ± . HO F –CL41 0 7 Glucocorticoid H pb 74–94% Mwt 392.9 Metabolism: reduction of ur – PSA 94.8 A˚ 2 noncyclic ketone to alcohol H H log P 1.34 O Cl

1/ ∗ t 2 4.4–5.8 h V 4.4–4.7 MOMETASONE ∗ O Cl F <1% CL 12 iv OH < HO pb 98–99% Mwt 427.4 Furoate: F 1% 2 H ur Low PSA 74.6 A˚ Antiinﬂammatory log P 2.68 Metabolism: reduction of Cl H ketone, formation of epoxide O from 2-chloroethanol, allylic hydroxylation

1/ . ± . . ± . t 2 3 6 0 4h V 0 97 0 11 PREDNISONE F 80±11% CL 3.6±0.8 (CYCLOHEXANONE) or O OH ∗ ∗ OH pb 75±2% Mwt 360.44 PREDNISOLONE HO ur 3±2% PSA 94.8 A˚ 2∗ (CYCLOHEXANOL, H log P 1.64∗ DRAWN) H H Glucocorticoid O Prednisone and prednisolone are interconverted in vivo

1/ O OH t 2 1.3–1.9 h V 0.3–0.6 HYDROCORTISONE, F 75–100% CL 3.1–4.3 CORTISOL HO OH pb 90% Mwt 362.5 Glucocorticoid, crosses bbb H ur <1% PSA 94.8 A˚ 2 H H log P 1.76 O

1/ . ∗ O OH t 2 1.2 h V 0 3 CORTISONE F –CL–∗ O OH acetate pb 95%∗ Mwt 360.4 H Glucocorticoid, ur – PSA 91.7 A˚ 2 antiinﬂammatory H H log P 1.43 O

1/ . ± . . ± . t 2 2 0 0 7h V 1 3 0 7 TRIAMCINOLONE O OH ± . ± . O F 23 10% CL 7 7 2 6 ACETONIDE HO pb 40% Mwt 434.5 Glucocorticoid H O ur 1.0±0.6% PSA 93.1 A˚ 2 Metabolism: F H log P 2.43 6-hydroxylation, oxidation to O 21-carboxy, no acetal hydrolysis (continued overleaf ) 480 66 Steroids

t1/ 2–3 h (iv) V 2.9±1.5 BUDESONIDE O OH 2 O F 12±3% CL 17±4 Antiinﬂammatory HO O pb 88% Mwt 430.5 Metabolism: allylic H ˚ 2 H ur 2% PSA 93.1 A hydroxylation, cyclopentane H H log P 3.20 hydroxylation (at CH–O) O

1/ O t 2 0.7 h V 2.9 CICLESONIDE F <0.5% CL 39 Antiinﬂammatory O O pb 99% Mwt 540.7 High ﬁrst-pass metabolism O 2 HO ur – PSA 99.1 A˚ (ester hydrolysis) H O log P 6.13 H H H O

1/ t 2 6–7 h V 12.1 DES-CICLESONIDE HO O F 1% CL 59 Main active metabolite of O HO pb 99% Mwt 470.6 ciclesonide ur <20% PSA 93.1 A˚ 2 H O H log P 4.14 H H O

1/ ∗ HO t 2 1.4–1.7 h V 1.4–1.9 FLUNISOLIDE O ∗ F 6–10% CL 13.7–14.3 iv O HO pb 80% Mwt 434.5 Antiasthmatic ur – PSA 93.1 A˚ 2 Metabolism: displacement H O H log P 2.04 of allylic ﬂuoride by OH H H O F

1/ t 2 1.3–1.7 h V – FLUOCINOLONE HO O F Low CL – ACETONIDE O HO pb – Mwt 452.5 Topical antiinﬂammatory ur – PSA 93.1 A˚ 2 Acetonide: improves H O H log P 2.23 absorption by skin F H O F 481

1/ t 2 1–2 h V 1 FLUOCORTOLONE O F >90% CL 6.5±2.1 Glucocorticoid, pb 83–95% Mwt 376.5 immunosuppressant HO OH ur Low PSA 74.6 A˚ 2 Metabolism: elimination of H log P 1.83 ﬂuoride, substitution of H H ﬂuoride by OH, O glucuronidation, sulfation, F oxidation of secondary alcohol to ketone

t1/ 1.1–1.9 h V 1.2–1.5 DEFLAZACORT AcO O 2 F 68% CL – Antiinﬂammatory N HO pb 40% Mwt 441.5 Prodrug of ˚ 2 H O ur 18% PSA 102 A desacetyldeﬂazacort; all H log P 2.05 values for metabolite H H O

1/ F t 2 7.8 h (iv) V 4.2–11.1 FLUTICASONE S O F <1% CL 12.8–22.7 Propionate: F <2% . HO OH pb 90% Mwt 444.5 Furoate: F 1 6% < 2 H ur 0.02% PSA 99.9 A˚ Antiallergic, log P 2.07 antiinﬂammatory F H Metabolism: hydrolysis of O ester, displacement of allylic F ﬂuoride by OH

1/ O t 2 30–40 h V 20 CYPROTERONE ACETATE O F 88–100% CL 3.6 Antiandrogen, treatment of pb 95% Mwt 416.9 acne H O ur 33% PSA 60.4 A˚ 2 Metabolite: 15-β-hydroxy- H H log P 4.22 and 3-α-hydroxycyproterone O Cl

t1/ 1–2 h V 4ELCOMETRINE O O 2 F 10% CL – Contraceptive O pb – Mwt 370.5 H H ur – PSA 60.4 A˚ 2 log P 3.00 H H O

(continued overleaf ) 482 66 Steroids

1/ ∗ O t 2 40–60 h V 3.7 MEDROXYPROGESTERONE F <10% CL – ACETATE O pb 86–95% Mwt 386.5 ∗im: 2 wk H O ur 1% PSA 60.4 A˚ 2 Crosses bbb log P 4.17 Metabolism: reduction of H H enone to enol, then O glucuronidation

1/ O t 2 15–20 h V – MEGESTROL ACETATE F –CL–Progestogen, appetite O pb – Mwt 384.5 stimulant H O ur 50–70% PSA 60.4 A˚ 2 Metabolism: hydroxylation log P 3.75 of cyclopentyl-CH H H 3 O

1/ O t 2 25–39 h V 2–3 CHLORMADINONE OH F 24% CL – Contraceptive pb >95% Mwt 362.9 Metabolism: reduction of H ur – PSA 54.4 A˚ 2 cyclohexenone to H H log P 3.27 cyclohexenol, O 2-hydroxylation; withdrawn Cl in 1972 because of carcinogenicity

1/ O t 2 12–17 h V – MEDROXYPROGESTERONE F –CL–Progestogen OH pb 86–90% Mwt 344.5 H ur – PSA 54.4 A˚ 2 log P 3.58 H H O

1/ O t 2 20 min V 0.3–0.5 PROGESTERONE F <20% CL – Progestogen, crosses bbb pb 95–98% Mwt 314.5 Metabolism: hydrogenation H ur – PSA 34.1 A˚ 2 of alkene and of enone to log P 3.83 enol H H O

1/ O t 2 5–7 h V – DYDROGESTERONE F 28% CL – Progestogen pb 97% Mwt 312.5 Active metabolite: H ur – PSA 34.1 A˚ 2 20α-dihydrodydrogesterone log P 3.55 (t1/ 14–17 h) H H 2 O 483

1/ O t 2 36 h V – MEDROGESTONE F 100% CL – Progestogen pb – Mwt 340.5 H ur – PSA 34.1 A˚ 2 H H log P 4.35 O

1/ O t 2 4.7 h (iv) V 2 ELTANOLONE, F Low CL 22 PREGNANOLONE pb 99% Mwt 318.5 Local anesthetic H ur Negligible PSA 37.3 A˚ 2 Metabolism: H H log P 5.04 glucuronidation, reduction HO of ketone to alcohol H

1/ O t 2 0.1–0.5 h V – ALPHAXALONE F –CL–Sedative, anesthetic, O pb 40% Mwt 332.5 anticonvulsant H ur – PSA 54.4 A˚ 2 Metabolism: H H log P 3.28 glucuronidation HO H

1/ N t 2 5–14 h V – ABIRATERONE F Low CL 79 CYP17 inhibitor, oncolytic; pb >99% Mwt 349.5 prodrug: acetate ur – PSA 33.1 A˚ 2 Metabolism: N-oxidation, H log P 5.70 O-sulfation H H HO

1/ / . ∗ O t 2 37–70 h V F 3 2 GANAXOLONE F –CL–∗rat pb – Mwt 332.5 GABA receptor modulator, H ur – PSA 37.3 A˚ 2 sedative, antiepileptic H H log P 5.42 HO H

1/ ∗ t 2 25 h V – NORGESTIMATE F 22%∗∗ CL – ∗desacetyl metabolite pb – Mwt 369.5 ∗∗levonorgestrel on oral O ur – PSA 58.9 A˚ 2 dosing of norgestimate H O log P 5.13 Not detectable in plasma H H after oral dosing HO N Metabolism: O-deacetylation, hydrolysis of oxime (to levonorgestrel) (continued overleaf ) 484 66 Steroids

1/ t 2 – V – DESOGESTREL F 62–75%∗ CL 2.4 Oral contraceptive; rapid OH pb – Mwt 310.5 oxidation by CYP2C9 to H ur – PSA 20.2 A˚ 2 etonogestrel; log P 5.35 ∗etonogestrel on oral H H administration of desogestrel

1/ t 2 24–30 h V 7.2 ETONOGESTREL, OH F 82% CL 2.6 3-KETODESOGESTREL pb 96–99% Mwt 324.5 Active metabolite of H ur – PSA 37.3 A˚ 2 desogestrel H H log P 3.32 O

1/ . ± . . ± . t 2 8 5 2 6h V 3 6 1 7 NORETHINDRONE, HO F 64±14% CL 5.9±1.1 NORETHISTERONE pb 94±3% Mwt 298.4 Progestogen, oral H H ur <4% PSA 37.3 A˚ 2 contraceptive H H log P 2.86 Metabolism: reduction of O ketone to alcohol, hydrogenation of alkene

1/ ± t 2 15 3h V 1.7 LEVONORGESTREL . ± . OH F 94% CL 1 5 0 6 Progestogen, oral pb 37±7% Mwt 312.5 contraceptive H ur 52±8% PSA 37.3 A˚ 2 Metabolism: hydrogenation H H log P 3.37 of ketone and alkene, O 16-hydroxylation

1/ t 2 12–18 h V 0.24–1.2 GESTODENE OH F 100% CL 0.8–0.9 Oral contraceptive, pb 98–99% Mwt 310.4 progestogen H H ur <1% PSA 37.3 A˚ 2 Metabolism: reduction of H H log P 2.02 ketone to alcohol O

1/ t 2 5.7–6.4 h V – TIBOLONE F –CL–Synthetic steroid for OH pb – Mwt 312.5 hormone replacement ur – PSA 37.3 A˚ 2 therapy H log P 3.52 Metabolism: reduction of ketone to active 3-α (t1/ 27 h, H H 2 monkey) and 3-β (t1/ 17 h, O 2 monkey) hydroxy metabolites 485

1/ t 2 24 h V 3.4 DANAZOL OH F Low CL – Antigonadotropin pb – Mwt 337.5 Metabolism: reductive H ur – PSA 46.3 A˚ 2 cleavage of isoxazole to N H H log P 4.94 2-hydroxymethylethisterone O and ethisterone

1/ ± . ± . t 2 10 6h V 3 5 1 0 ETHINYL ESTRADIOL ± . ± . OH F 51 9% CL 5 4 2 1 Estrogen, oral contraceptive pb 95–98% Mwt 296.4 Metabolism: aromatic H ur 1–5% PSA 40.5 A˚ 2 2-hydroxylation, then H H log P 4.11 O-methylation HO

1/ t 2 9.3 h (iv) V 0.61 ETHINYL O OH F –CL1.3ESTRADIOL-17-SULFATE S pb – Mwt 376.5 Metabolite of ethinyl H O O ur – PSA 83.8 A˚ 2 estradiol H H log P 1.33 HO

1/ t 2 8.4 h (iv) V 2.3 ETHINYL OH F –CL4.7ESTRADIOL-3-SULFATE pb 99% Mwt 376.5 Metabolite of ethinyl H ur – PSA 92.2 A˚ 2 estradiol O O H H log P 3.29 S HO O

1/ t 2 0.8–1.0 h V 2 MESTRANOL OH F –CL–Prodrug of ethinyl estradiol, pb – Mwt 310.4 contraceptive H ur – PSA 29.5 A˚ 2 Metabolism: H H log P 4.94 O-demethylation MeO

1/ OH t 2 2–10 h V – FLUOXYMESTERONE HO F <44% CL – Androgen H pb 99% Mwt 336.4 Metabolism: hydrogenation ˚ 2 = F H ur – PSA 57.5 A of ketone and C C double log P 2.27 bond, hydroxylation O

(continued overleaf ) 486 66 Steroids

1/ OH t 2 1–2 h V 1 TESTOSTERONE F 4.3% CL 12.9 Natural androgen, crosses H pb 98% Mwt 288.4 bbb ur – PSA 37.3 A˚ 2 Metabolism: hydrogenation H H log P 3.18 of alkene O

1/ OH t 2 2–4 h V 1.0 ESTRADIOL F 3–5% CL 30 Natural estrogen, crosses H pb 97–99% Mwt 272.4 bbb; active metabolites: ur – PSA 40.5 A˚ 2 estrone, estriol; prodrug H H log P 4.15 estradiol valerate: same oral HO bioavailability as estradiole

1/ OH t 2 9–10 h V –ESTRIOL F –CL–Natural estrogen H OH pb – Mwt 288.4 Metabolites: ur – PSA 60.7 A˚ 2 16-hydroxyestrone, H H log P 2.53 glucuronides HO

1/ ∗ OH t 2 40–50 d V 3–5 FULVESTRANT F Low CL ∗im H pb 99% Mwt 606.8 Antineoplastic ur <1% PSA 76.7 A˚ 2 H H Metabolism: aromatic log P 7.92 hydroxylation, HO ()9 F F S glucuronidation, sulfation O CF3

1/ CN t 2 8–9 h V 0.6 DIENOGEST F 91% CL 0.7 Progestogen, oral OH pb 90% Mwt 311.4 contraceptive H ur <1% PSA 61.1 A˚ 2 Metabolism: hydroxylation log P 2.58 H O

t1/ 24–27 h V 1.8∗ EXEMESTANE O 2 F 5–60% CL/F 147 ∗dog H pb 90% Mwt 296.4 Reductase inhibitor, ur <1% PSA 34.1 A˚ 2 antineoplastic H H log P 2.43 Metabolism: reduction of O cyclopentanone to cyclopentanol 487

1/ t 2 18 min (iv) V 1.8 FORMESTANE O ∗ F 20–25%∗ CL 2–3 im H pb 82–86% Mwt 302.4 Antineoplastic ur Negligible PSA 54.4 A˚ 2 Metabolism: H H log P 1.79 glucuronidation of enol, O reduction of cyclohexenone OH to cyclohexenol, then conjugation

1/ < O t 2 1h V 2 ISTAROXIME F –CL60 NH Inotropic, lusitropic 2 H pb – Mwt 360.5 ur – PSA 81.8 A˚ 2 H H O log P 1.89 N H O

t1/ >240 h V 4.6–7.7 DUTASTERIDE O H CF3 2 N F 40–94% CL 0.15 5α-Reductase inhibitor pb >99% Mwt 528.5 Metabolism: hydroxylation H ur <1% PSA 58.2 A˚ 2 log P 5.61 H H F3C O N H H

1/ . ± . . ± . O H t 2 7 9 2 5h V 1 1 0 2 FINASTERIDE N F 63±21% CL 2.3±0.8 5α-Reductase inhibitor, pb 93% Mwt 372.5 CYP3A4 substrate H ur <1% PSA 58.2 A˚ 2 Metabolism: H H log P 3.83 CH3-hydroxylation, then O N oxidation of CH3 to CO2H H H

1/ O H t 2 26 h V 0.54 EPRISTERIDE N F 93% CL 0.33 5α-Reductase inhibitor for pb 97% Mwt 399.6 treatment of benign H ur – PSA 66.4 A˚ 2 prostatic hypertrophy H H log P 5.34

HO2C

1/ O t 2 1.4 h V 1.8 SPIRONOLACTONE F >90% CL 4.2±1.7 Diuretic O pb >90% Mwt 416.6 Metabolism: deacetylation, H H ur <1% PSA 85.7 A˚ 2 then S-methylation, log P 3.15 elimination of thioacetyl (to H H yield diene = canrenone) O S

(continued overleaf ) 488 66 Steroids

1/ . ± . O t 2 3 9 1 2h V – CANRENONE F 25±9% CL 4.2±1.7 Diuretic O pb – Mwt 340.5 Metabolite of spironolactone H H ur – PSA 43.4 A˚ 2 log P 3.51 H H O

1/ O t 2 4–6 h V 0.6–1.3 EPLERENONE F –CL2.6Antihypertensive O pb 49% Mwt 414.5 Metabolism: lactone O H ur <2% PSA 82.2 A˚ 2 hydrolysis, ester hydrolysis, log P 1.05 6β- and 21-hydroxylation H

O CO2Me

1/ . ± . O t 2 35–39 h V 3 7 4 2 DROSPIRENONE F 76–85% CL 1.2–1.5 Progestogen O pb 95–98% Mwt 366.5 Metabolism: ring-opening H ur Negligible PSA 43.4 A˚ 2 of lactone, hydrogenation of log P 3.39 alkene, sulfation H H O

1/ t 2 11–13 h V – DIHYDROTACHYSTEROL F –CL–Vitamin D analog H pb >99% Mwt 398.7 Metabolism: dihydroxylation OH ur – PSA 20.2 A˚ 2 log P 9.66 H

1/ t 2 19–48 h V – ERGOCALCIFEROL, F 55–99% CL – Vitamin D H 2 pb >99.8% Mwt 396.7 ur – PSA 20.2 A˚ 2 log P 9.15 H HO

1/ OH t 2 10–22 d V – CALCIFEDIOL F –CL–Calcium regulator H pb 98% Mwt 400.6 Metabolite: calcitriol ur – PSA 40.5 A˚ 2 log P 7.08 H HO 489

1/ t 2 32–96 h V – DOXERCALCIFEROL, F 42% CL – 1α-HYDROXYVITAMIN D H 2 pb >99% Mwt 412.7 Vitamin D2 analog HO ur – PSA 40.5 A˚ 2 Metabolite: log P 7.70 1,25-dihydroxyvitamin D2 H HO

1/ OH t 2 5–15 h V 0.4 PARICALCITOL F 72% CL 0.9 Vitamin D analog H pb >99% Mwt 416.6 Metabolism: hydroxylation, HO ur 0% PSA 60.7 A˚ 2 dihydroxylation of oleﬁns, log P 5.83 glucuronidation H HO

1/ t 2 3h V – ALFACALCIDOL, 1- F 71% CL – HYDROXYCHOLECALCIFEROL H pb >99% Mwt 400.6 Vitamin D analog HO ur – PSA 40.5 A˚ 2 Metabolism: hydroxylation log P 7.64 to calcitriol H HO

1/ < t 2 2h V – CALCIPOTRIOL F 5–6% CL – Vitamin D analog for H pb – Mwt 412.6 treatment of psoriasis OH OH ur – PSA 60.7 A˚ 2 Metabolism: oxidation of log P 5.43 cyclopropylmethanol to H ketone, then hydrogenation HO of enone to saturated ketone

1/ . ∗ OH t 2 3–6 h V 0.2–0 4 CALCITRIOL, ∗ F 62% CL 6–21 VITAMIN D3 H ∗ pb >99% Mwt 416.6 dog HO ur – PSA 60.7 A˚ 2 log P 5.63 H HO

1/ HO t 2 3.0–4.9 h V – ASOPRISNIL N O F –CL–Progesterone receptor OMe pb – Mwt 449.6 modulator; active H < ˚ 2 1/ ur 0.2% PSA 68.1 A metabolite: t 2: 4–5 h; log P 4.11 further metabolism: H O-demethylation O

(continued overleaf ) 490 66 Steroids

1/ ± ∗ t 2 32 6h V – ULIPRISTAL ACETATE N ∗ O F 56% CL 20 ulipristal O pb 97–99% Mwt 475.6 Contraceptive ur – PSA 63.7 A˚ 2 Metabolism: deacetylation to H O log P 4.48 ulipristal, N-demethylation, H hydroxylation O

1/ t 2 15–48 h V 0.4–0.7 MIFEPRISTONE N F 40–70% CL 0.7 Abortifacient HO pb 94–99% Mwt 429.6 Metabolism: ur Negligible PSA 40.5 A˚ 2 N-demethylation, H log P 6.19 hydroxylation of propargylic H CH3, then oxidation to O aldehyde

1/ t 2 16–52 h V 4.7–6.8 TIRILAZAD F <12% CL 5.6–10.5 Lipid peroxidation inhibitor N pb >99% Mwt 624.9 Metabolism: hydrogenation ˚ 2 N N N ur – PSA 72.9 A of 4–5 alkene (enone), N O log P 4.89 hydroxylation N H

H O

1/ . ± . . ± . OAc t 2 2 3 0 4h V 0 26 0 07 PANCURONIUM F –CL1.8±0.4 Neuromuscular blocking H N pb 7±2% Mwt 572.9 agent N ur 67±18% PSA 52.6 A˚ 2 Metabolism: deacetylation H H log P −1.62 AcO H

1/ . ± . . ± . OAc t 2 1 5 0 7h V 0 21 0 08 VECURONIUM F –CL3.0±0.1 Neuromuscular blocking H N pb 30±9% Mwt 557.8 agent N ur 18±5% PSA 55.9 A˚ 2 Metabolism: O-deacetylation H H log P 2.35 AcO H

1/ t 2 2h V 0.3–0.4 RAPACURONIUM O F – CL 5–9 Neuromuscular blocking O pb 50–88% Mwt 597.9 agent ur 8% PSA 55.8 A˚ 2 Metabolism: H N N log P 2.32 O-deacetylation; withdrawn H H in 2001 for causing fatal AcO bronchospasm H 491

1/ OAc t 2 2.2–3.4 h V 0.18–0.28 ROCURONIUM F – CL 2.8–4.0 Neuromuscular blocking O H N pb 25% Mwt 529.8 agent N ur 9–22% PSA 59.0 A˚ 2 Metabolism: deacetylation H H log P 0.73 HO H

1/ . ± . . ± . OAc t 2 2 5 1 5h V 0 35 0 08 PIPECURONIUM, F –CL2.1±0.5 PIPECURIUM N H N N pb – Mwt 602.9 Neuromuscular blocking N ur 37–41% PSA 59.1 A˚ 2 agent H H log P −3.66 Metabolism: deacetylation AcO H

1/ t 2 4–15 h V 0.3 FUSIDIC ACID CO H F 91% CL – Antibiotic H 2 HO pb 98–99% Mwt 516.7 Metabolism: oxidation of ur <0.1% PSA 104 A˚ 2 allylic CH groups, O 3 log P 5.76 glucuronidation H O HO H

1/ t 2 56–70 h V 0.2 BEVIRIMAT F 22–24%∗ CL 0.05 ∗rat H pb >99.5% Mwt 584.8 HIV-1 maturation inhibitor ur <1% PSA 101 A˚ 2 Metabolism: CO2Me H CO2H log P 10.2 glucuronidation H O O H

67 Anthracyclines

Tetracycline antibiotics, produced by Streptomyces aureofaciens and Streptomyces rimosus, are active against in a broad spectrum of bacteria. The ﬁrst tetracycline, chlortetracycline, was introduced in 1948. These compounds inhibit bacterial protein synthesis by binding to the bacterial 30S ribosome. Being highly oxidized and heteroatom rich, tetracyclines undergo few metabolic transformations. The anthracycline antibiotics daunorubicin and doxorubicin are also produced by a fungus (Streptomyces peucetius). These DNA intercalators have become valuable antitumor agents. However, as DNA/RNA-damaging agents, anthracyclines are mutagenic and carcinogenic as well. Because these natural products also show high cardiotoxicity, numerous analogs have been prepared, some with improved therapeutic index (Table 67.1).

Table 67.1 Anthracyclines and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

t1/ 15–45 h V 13–52 EPIRUBICIN NH2 2 OH F Low CL 7.1–23.8 Antineoplastic pb 75% Mwt 543.5 Metabolism: glucuronidation, ˚ 2 MeO O OH O O ur 6–7% PSA 206 A reduction of nonaromatic ketone to log P 0.24 alcohol

OH HO O OH O

t1/ 26±17 h V 17±11 DOXORUBICIN NH2 2 ± OH F 5% CL 17 8 Antineoplastic pb 70–85% Mwt 543.5 Prodrug: N-L-leucyl-doxorubicin < ˚ 2 MeO O OH O O ur 7% PSA 206 A log P 0.24

OH HO O OH O

t1/ 20–30 h V 39 DAUNORUBICIN NH2 2 OH F Low CL 15–30 Antineoplasitc (leukemia); does not pb 50–60% Mwt 527.5 cross bbb ur 5–18% (iv) PSA 186 A˚ 2 Metabolism: reduction of ketone, MeO O OH O O log P 0.54 O-demethylation, glycosidic cleavage, O-sulfation, O-glucuronidation HO O OH O

1/ NH2 t 2 6–35 h V 37–64 IDARUBICIN, OH F 18–39% CL 17–24 4-DEMETHOXYDAUNORUBICIN pb 97% Mwt 497.5 Antineoplastic, crosses bbb < ˚ 2 O OH O O ur 5% PSA 177 A Metabolite: 13-dihydro 1/ log P 1.44 (idarubicinol, t 2 81 h; pb 94%; ur < 5%)

HO O OH O

1/ ± ± OH O OH OMe t 2 11 6h V 30 9 MENOGARIL F 32±12% CL 17±7 Antineoplastic pb – Mwt 541.6 Metabolism: N-demethylation OH ur 17% (iv) PSA 166 A˚ 2 HO O O O log P 3.16

Me2N HO

1/ ± . ± . H t 2 16 6h V 0 75 0 32 DOXYCYCLINE HO O HO O O . ± . O F 93% CL 0 53 0 18 Antibacterial pb 88±5% Mwt 444.4 NH 2 ur 41±19% PSA 182 A˚ 2 OH log P 1.78 H H O NH H 2

1/ . ± . . ± . H t 2 10 6 1 5h V 1 5 0 1 TETRACYCLINE HO O HO O O . ± . O F 77% CL 1 67 0 24 Antibacterial pb 65±3% Mwt 444.4 NH2 ur 58±8% PSA 182 A˚ 2 OH log P 0.62 H H HO N

(continued overleaf ) 494 67 Anthracyclines

1/ H t 2 14 h V – METHACYCLINE HO O HO O O < O F 60% CL – Antibacterial pb 78% Mwt 442.4 NH 2 ur 25% PSA 182 A˚ 2 OH log P 1.35 H H O N H

1/ t 2 5–9 h (iv) V 0.54 ROLITETRACYCLINE H Antibacterial, prodrug of HO O HO O O N F Low CL 0.97 O pb 50% Mwt 527.6 tetracycline N ur >50% (iv) PSA 171 A˚ 2 H log P 1.66 OH H H HO N

1/ ∗ − . ∗ H N t 2 9–12 h V 1.3 1 6 LYMECYCLINE 2 ∗ H F 70–80% CL – Antibacterial HO O HO O O HN CO H ∗ O 2 pb 55–64% Mwt 602.6 Prodrug of tetracyclin; prodrug can ∗ N ur 25% PSA 243 A˚ 2 not be detected in plasma after oral H log P 0.75 dosing OH ∗ H H tetracycline upon oral dosing of HO N prodrug

1/ H t 2 7h(iv) V 0.9 CHLORTETRACYCLINE HO O HO O O O F –CL2 Metabolism: epimerization, pb 48% Mwt 478.9 N-demethylation NH2 ur – PSA 182 A˚ 2 OH log P 1.32 H H Cl O N H

1/ H t 2 14 h V 1.3 DEMECLOCYCLINE HO O HO O O O F 60–80% CL 1.1 Antibacterial pb 41–50% Mwt 464.9 NH2 ur 30–50% PSA 182 A˚ 2 OH log P 0.94 H H Cl OH N

1/ H t 2 10 h (iv) V 1.7 OXYTETRACYCLINE HO O HO O O O F 3% (pig) CL 2.0 Antibacterial pb 10% Mwt 460.4 Metabolism: N-demethylation, NH2 ur – PSA 202 A˚ 2 epimerization OH log P 0.48 H H HO O N H 67 Anthracyclines 495

1/ ± . ± . H t 2 16 2h V 1 3 0 2 MINOCYCLINE HO O HO O O O F 95–100% CL 1.0±0.3 Antibacterial pb 76% Mwt 457.5 Metabolism: 9-hydroxylation, NH2 ur 11±2% PSA 165 A˚ 2 N-demethylation OH log P 2.12 H H N N

1/ ∗ t 2 37–67 h V 7–9 TIGECYCLINE F Low CL 3.3–5.0 ∗iv HN pb 71–89% Mwt 585.7 Antibacterial O H 2 OH O HO O O ur 15% (iv) PSA 206 A˚ Metabolism: glucuronidation, O − . HN log P 0 85 glycinamide hydrolysis, then NH2 N-acetylation OH H H N N

1/ / H t 2 57 h V F 0.63 METASTAT, COL-3 OH O HO O O O F –CL/F 0.13 Matrix metalloproteinase inhibitor, pb 95% Mwt 371.3 antineoplastic NH2 ur PSA 158 A˚ 2 OH log P 0.84 H H

1/ . ± . O t 2 3 5 1 1h V – AMLEXANOX F –CL–Antiallergic, antiasthmatic CO2H pb – Mwt 298.3 Metabolism: hydroxylation of 2 ur 17% PSA 103 A˚ CH(CH3)2, then conjugation O N NH2 log P 3.74

1/ O OH t 2 12 h V –ALIZARIN OH F –CL–Biological stain pb – Mwt 240.2 Metabolism: O-glucuronidation ur 18–36% PSA 74.6 A˚ 2 log P 2.91 O

1/ ∗ O t 2 4–8 h V – DIACEREIN, DIACETYLRHEIN ∗ ∗rhein upon oral dosing of CO2H F 35% CL – pb 99%∗ Mwt 368.3 diacerein ur 20%∗ PSA 124 A˚ 2 Antiarthritic log P 3.13 Metabolism: deacetylation to rhein, O O O then glucuronidation, sulfation O O

(continued overleaf ) 496 67 Anthracyclines

1/ t 2 3–5 h (iv) V – HYCANTHONE N F Low CL – Hydroxylated metabolite of O HN pb – Mwt 356.5 lucanthone, anthelmintic ur – PSA 77.9 A˚ 2 Metabolism (monkey): log P 3.81 N-deethylation S

NH t1/ 12–32 h V 10–30 PIXANTRONE O HN 2 2 F Low CL 13–22 Intercalator, topoisomerase II pb 57% Mwt 325.4 inhibitor, antineoplastic, N ur <10% PSA 123 A˚ 2 immunosuppressant log P 1.82 O HN NH2

H 1/ N t 2 10–18 d V 15–32 MITOXANTRONE OH O HN OH F – CL 4.7–14 Antineoplastic, does not cross bbb pb 75% Mwt 444.5 Metabolism: oxidation to ur 4% PSA 163 A˚ 2 dicarboxylic acid log P 1.55 OH O HN OH N H

H 1/ ∗ N t 2 24–51 h V 21–39 LOSOXANTRONE, CI 941 OH O HN OH F – CL 12–20 ∗iv pb 92–97% Mwt 425.5 Antineoplastic ur <8% PSA 132 A˚ 2 Metabolism: 2- and 4-hydroxylation log P 1.99 of phenol N N OH N H

OH O HN NH 1/ 2 t 2 0.5 h (iv) V 0.8 PIROZANTRONE, F –CL34OXANTRAZOLE pb – Mwt 411.5 Antineoplastic ur 5% (iv) PSA 141 A˚ 2 OH N N OH N log P 1.96 H

1/ N t 2 45 h (iv) V 57 TOPIXANTRONE O HN F –CL27Antineoplastic pb – Mwt 394.5 < ˚ 2 N ur 10% (iv) PSA 90.4 A log P 1.31 N N OH N H

68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDS)

Aryl- and heteroarylacetic acids and the closely related 2-arylpropionic acids are an important class of nonsteroidal antiinflammatory drugs (NSAIDs). A large number of drugs of this type have been developed (Table 68.1), but most of them show similar biological properties and no significant advantages if compared to the rest. One of the first examples of this class of NSAIDs was ibuprofen, launched in 1964, which resulted from the screening of more than 600 alkanoic acids for antiinflammatory activity. Although the goal was a nonulcerogenic analgesic or antipyretic, ibuprofen was again burdened with this side effect, which seems to be inherent to all cyclooxygenase-1-inhibiting NSAIDs. Prostaglandines have a strong gastroprotective effect, and the suppression of their biosynthesis by inhibition of COX-1 (cyclooxygenase) inevitably increases the risk of gastric lesions. Most of the drugs listed below undergo acyl glucuronidation in vivo and are then excreted in the urine and bile.

68.1 Salicylates

The use of willow bark extracts for the treatment of pain and fever was reported as early as 1554. Salicin (Scheme 68.1), the active glycoside of the willow bark, was isolated in pure form in 1829 and used for the treatment of rheuma until the 1950s.

OH O OH O OH O O HO HO O

HO OH O OH Salicin Salicylic acid Aspirin Metabolism: hydrolysis of acetal and oxidation to salicylic acid

Scheme 68.1

Adolph Kolbe synthesized salicylic acid in 1874 and arranged to have Carl Emil Buss (St. Gallen, Switzerland) test it in typhoid patients as an alternative to the

antiseptic phenol. Buss found that salicylic acid, despite its phenol substructure, was not antiseptic, but lowered fever instead. This discovery led to the large-scale production and marketing of salicylic acid as antipyretic. Unfortunately, salicylic acid causes stomach irritation and has such a bad taste that it may induce vomiting. With the aim of finding a better-tasting compound, the chemist Felix Hoffmann prepared (the known) acetylsalicylic acid in 1897 at Bayer. This compound, later named aspirin, turned out to be superior to salicylic acid and became the most widely used antipyretic [1]. Salicylates and other nonsteroidal antiinflammatory drugs (NSAIDs; 4-aminophenols, aryl/heteroarylacetic acids, and oxicams) suppress the biosynthesis of prostaglandins by inhibiting the cyclooxygenases (COX-1 and COX-2). One common side effect of all COX-1 inhibitors is their tendency to cause gastric damage (ulcers and erosions), as prostaglandins play an important role in the maintainance of the gastric mucosa. This does not seem to be the case for COX-2 inhibitors, which, however, seem to cause heart damage by increasing the viscosity of blood [2]. Numerous derivatives and analogs of salicylic acid have been marketed as antipyretics (Table 68.2), but none excelled aspirin. Anthranilic acid (2- aminobenzoic acid) is devoid of antipyretic effect, but 2-(arylamino)benzoic acids are potent analgetics and antiinflammatories.

References

1. (a) Sneader, W. (1995) Salicylates and their analogues. Drug News Perspect., 8, 644–648; (b) Sneader, W. (1996) Antipyretic analgesics. Drug News Perspect., 9, 61–64; (c) Sneader, W. (1996) Nonsteroidal antiinﬂammatory drugs. Drug News Perspect., 9, 181–185. 2. Blobaum, A.L. and Marnett, L.J. (2007) Structural and functional basis of cyclooxygenase inhibition. J. Med. Chem., 50, 1425–1441.

Table 68.1 Arylacetic acids, arenecarboxylic acids, and related compounds. V inlkg−1,CLin ml min−1 kg−1, Mwt in g mol−1.

1/ ± ± t 2 2.0 0.5 h V/F 0.15 0.02 IBUPROFEN F >80% CL/F 0.75±0.20 Antiinﬂammatory, racemate pb >99% Mwt 206.3 Metabolism: glucuronidation, ur <1% PSA 37.3 A˚ 2 conversion to CoA-thioester, CO H log P 3.50 hydroxylation of isobutyl group 2 at all positions, oxidation of (CH3)2CH to HO2C(CH3)CH; prodrug: hydroxamic acid (ibuproxam)

1/ t 2 – V – LOXOPROFEN F –CL– Antiinﬂammatory O CO2H pb 97% Mwt 246.3 Metabolism: reduction of ketone ˚ 2 1/ ur – PSA 54.4 A to alcohol (t 2 1.3 h) log P 1.87 499

1/ t 2 1.6–3.8 h V 0.26 XIMOPROFEN F 98% CL 1.6 Antiinﬂammatory CO H 2 pb 93% Mwt 261.3 Metabolism: hydrolysis of oxime N HO ur 25% PSA 69.9 A˚ 2 to ketone, then reduction to log P 2.31 alcohol

1/ t 2 2–4 h V 0.17 ALMINOPROFEN F – CL 0.5–1.0 Antiinﬂammatory CO H 2 pb – Mwt 219.3 N ur – PSA 49.3 A˚ 2 H log P 2.51

1/ ± t 2 6 1h V 0.11–0.17 PIRPROFEN F –CL0.28Antiinﬂammatory Cl pb >99.5% Mwt 251.7 Metabolism: dehydrogenation to CO2H ur <5% PSA 40.5 A˚ 2 pyrrole, epoxidation and N log P 2.71 trans-dihydroxylation of alkene, N-dealkylation, then N-acetylation

1/ ± t 2 2.0 0.5 h V 0.1 ALCLOFENAC Cl F –CL– Analgesic, antipyretic, CO H 2 pb >99% Mwt 226.7 antiinﬂammatory 2 O ur 10–50% PSA 46.5 A˚ Metabolism: epoxidation and log P 2.77 dihydroxylation of alkene

1/ ± ± t 2 5.5 1.4 h V/F 0.15 0.02 FLURBIPROFEN F 92% CL/F 0.35±0.09 Antiinﬂammatory, racemate CO H 2 pb >99.5% Mwt 244.3 Metabolism: 3- and ur 2±1% PSA 37.3 A˚ 2 4-hydroxylation of Ph, then F log P 3.66 conjugation

1/ ± ± t 2 14 1h V/F 0.16 0.02 NAPROXEN F 99% CL/F 0.13±0.02 Antiinﬂammatory CO2H pb 99.7±0.1% Mwt 230.3 Metabolites: glucuronide, ur <0.1% PSA 46.5 A˚ 2 O-desmethyl MeO log P 2.88

1/ ± t 2 3 1h V 0.11–0.17 INDOPROFEN F 100% CL – Antiinﬂammatory CO H O 2 pb 99% Mwt 281.3 Metabolism: glucuronidation N ur – PSA 57.6 A˚ 2 log P 2.82

(continued overleaf ) 500 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ ± t 2 6 2h V 0.18–0.21 INDOBUFEN F >75% CL 0.32 Antithrombotic > O CO2H pb 99% Mwt 295.3 Metabolism (rat): aromatic 5- ur 13% PSA 57.6 A˚ 2 and 6-hydroxylation of indolone, N log P 3.30 then conjugation

1/ ± ± t 2 1.8 0.3 h V 0.15 0.03 KETOPROFEN F 100% CL 1.2±0.3 Antiinﬂammatory, analgesic; O pb 99% Mwt 254.3 racemate < ˚ 2 CO2H ur 1% PSA 54.4 A Metabolism: 3- and log P 2.91 4-hydroxylation of Ph, reduction of ketone to alcohol, glucuronidation

1/ t 2 2.1 h V 0.04 SUPROFEN F 92% CL 0.76 Antiinﬂammatory pb >99% Mwt 260.3 Metabolism: reduction of ketone ur – PSA 82.6 A˚ 2 to alcohol, hydroxylation of O log P 2.18 thiophene, conjugation with S glucuronic acid or taurine, CO2H oxidative degradation of thiophene to 2-(4-carboxyphenyl)-propionic acid; withdrawn 1987 for causing ﬂank pain

1/ < ∗ t 2 1h V –AMFENAC ∗ O NH2 F –CL– monkey pb – Mwt 255.3 Antiinﬂammatory CO H 2 ur – PSA 80.4 A˚ 2 Metabolism: lactam formation, log P 2.23 glucuronidation, hydroxylation

1/ < ∗ t 2 1h V – NEPAFENAC F 6% (rat) CL – ∗monkey O NH2 pb 99% Mwt 254.3 Prodrug of amfenac (acid), 2 NH2 ur 0% PSA 86.2 A˚ ophthalmic antiinﬂammatory log P 1.04 Metabolism: hydrolysis of O amide, para-hydroxylation of aniline

1/ t 2 0.5–4.0 h V 0.1 BROMFENAC O NH2 F 67±20% CL 1–2 Antiinﬂammatory pb >99.8% Mwt 334.2 Metabolism: N-glucosidation, CO2H ur Low PSA 80.4 A˚ 2 acylglucuronidation, lactam Br log P 2.02 formation; withdrawn in 1998 because of hepatotoxicity 501

1/ ± t 2 2.5 0.5 h V 0.1 FENOPROFEN F 85% CL 0.13–0.60 Antiinﬂammatory O CO2H pb >99% Mwt 242.3 Metabolites: glucuronide, ur 30% PSA 46.5 A˚ 2 4-hydroxyphenoxy log P 3.72

1/ t 2 5h V –PRANOPROFEN F –CL– Antiinﬂammatory CO2H pb – Mwt 255.3 Metabolism: glucuronidation 2 N O ur 1.3% PSA 59.4 A˚ log P 1.34

1/ ∗ ∗ t 2 9.6 h V 1.2 ZALTOPROFEN S F 84%∗ CL 1.4∗ ∗rat CO2H pb 99.6% Mwt 298.4 Antiinﬂammatory ˚ 2 O ur 3% PSA 79.7 A Metabolism: glucuronidation, log P 4.25 S-oxidation to sulfoxide

1/ ± H t 2 21 6h V Small CARPROFEN N CO2H F 90% CL – Antiinﬂammatory pb 99% Mwt 273.7 Metabolism: glucuronidation ur 5–12% PSA 53.1 A˚ 2 Cl log P 3.84

CO H t1/ 7±4h V/F 0.36±0.13 ETODOLAC H 2 2 N F >80% CL/F 0.78±0.27 Antiinﬂammatory 8 O pb 99% Mwt 287.4 Racemate 7 ur <1% PSA 62.3 A˚ 2 Metabolites: glucuronide; 6- and 6 log P 3.42 7-hydroxy, 1-hydroxyethyl

1/ t 2 27–35 h V 0.15 BENOXAPROFEN F >95% CL – Antiinﬂammatory N pb >99.5% Mwt 301.7 Metabolism: glucuronidation (to CO2H Cl ˚ 2 1/ ur – PSA 63.3 A acylglucuronide, t 2 100 h); O log P 3.72 half-life is longer in elderly patients

1/ ± ∗ t 2 8 2h V 0.13–0.18 FLUNOXAPROFEN F –CL0.4∗monkey N CO H F 2 pb – Mwt 285.3 Antiinﬂammatory O ur 10% PSA 63.3 A˚ 2 Metabolism: acyl log P 3.18 glucuronidation

1/ O t 2 0.8 h (iv) V 0.19 ZONAMPANEL O F –CL5.3NMDA antagonist N CO H 2 pb – Mwt 331.2 Metabolism: reduction of NO to HN 2 ur 95% (iv) PSA 145 A˚ 2 hydroxylamine, then to amine log P 0.12 N N O2N

(continued overleaf ) 502 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ F O t 2 8h V – ZENARESTAT F 65% (dog) CL – Aldose reductase inhibitor NNCO2H pb >95% Mwt 441.6 Metabolism: glucuronidation ur 27% PSA 77.9 A˚ 2 Br O log P 4.36 Cl

1/ F t 2 13 h V – PONALRESTAT N F 90% CL – Aldose reductase inhibitor N CO2H pb – Mwt 391.2 Metabolism: glucuronidation ur – PSA 70.0 A˚ 2 Br O log P 2.70

1/ t 2 27–30 h V/F 0.2 ZOPOLRESTAT F >45% CL 0.08 Aldose reductase inhibitor for S N pb >99% Mwt 419.4 treatment of diabetic N CO2H ˚ 2 N ur 35–45% PSA 111 A complications O log P 3.01 Metabolism: glucuronidation, N-dealkylation (to F3C benzothiazole-2-carboxylic acid), aromatic hydroxylation, and dihydroxylation

t1/ 3–4 h V 0.16 BENDAZAC N O CO H 2 N 2 F –CL0.6Antiinﬂammatory pb >99% Mwt 282.3 Metabolites: 5-hydroxy, ur <10% PSA 64.3 A˚ 2 glucuronides log P 2.83

1/ t 2 3–12 h V – LONIDAMINE Cl ∗ F 50% CL – ∗monkey N CO2H N pb – Mwt 321.2 Antineoplastic ur High PSA 55.1 A˚ 2 Metabolite: acyl glucuronide Cl log P 4.63

1/ ± ± t 2 2.4 0.4 h V 0.29 0.04 INDOMETHACIN F 98±21% CL 1.4±0.2 Antiinﬂammatory O pb 90% Mwt 357.8 Metabolism: O-demethylation, ur 15±8% PSA 68.5 A˚ 2 N-deacylation, glucuronidation; N CO H 2 log P 4.25 hydroxamic acid of 1/ Cl indomethacin (oxametacine): t 2 11±1h OMe Metabolism: O-demethylation, glucuronidation, reductive N−O bond cleavage, debenzoylation; no hydrolysis to indomethacin 503

1/ ± O t 2 4.5 2.8 h V 1 ACEMETACIN

O CO2H F 66–100% CL – Antiinﬂammatory N pb 88% Mwt 415.8 Metabolism: glucuronidation, O 2 Cl ur – PSA 94.8 A˚ ester hydrolysis to log P 4.49 indomethacin, O-demethylation OMe

1/ ± ± O t 2 3.8 0.2 h V 0.28 0.03 CINMETACIN F –CL0.85±0.08 Antiinﬂammatory N CO2H pb – Mwt 349.4 Metabolism: hydrogenation of ur – PSA 68.5 A˚ 2 oleﬁn, O-demethylation, log P 3.91 N-deacylation

OMe

1/ ± ∗ t 2 15 4h V/F 2SULINDAC ∗ ∗ F 90% CL 1.5±0.9 ∗sulfide on oral dosing of CO H ∗ 2 pb 94±1% Mwt 356.4 sulindac S ur Negligible PSA 73.6 A˚ 2 Antiinflammatory O log P 2.55 Metabolism: oxidation to F sulfone, reduction to sulfide

t1/ 4.9±0.3 h V/F 0.54±0.07 TOLMETIN O 2 F >90% CL/F 1.3±0.3 Antiinﬂammatory N pb >99% Mwt 257.3 Metabolism: glucuronidation CO2H ur 7±3% PSA 59.3 A˚ 2 log P 2.68

1/ t 2 4–10 h V – ZOMEPIRAC F 100% CL 3.7–4.6 Antiinﬂammatory O pb 98–99% Mwt 291.7 Metabolism: glucuronidation, N ˚ 2 CO2H ur 5–20% PSA 59.3 A hydroxylation of CCH3, cleavage log P 3.36 to 4-chlorobenzoic acid; Cl withdrawn in 1983 for causing anaphylaxis

t1/ 5.3±1.2 h V 0.21±0.04 KETOROLAC O 2 F 90±10% CL 0.50±0.15 Antiinﬂammatory, analgesic N CO2H pb 99% Mwt 255.3 Metabolism: glucuronidation, ur 5–10% PSA 59.3 A˚ 2 4-hydroxylation of Ph log P 2.68

t1/ 2±1h V 0.04–0.17 TIAPROFENIC ACID O 2 F 95±5% CL 0.5–1.4 Antiinﬂammatory S pb 98–99% Mwt 260.3 Metabolism: reduction of ketone CO2H ur <5% PSA 82.6 A˚ 2 to alcohol, 4-hydroxylation of Ph log P 2.57 (continued overleaf ) 504 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ t 2 26–31 h V – FENCLOZIC ACID, MYALEX F –CL– Antiinﬂammatory, hepatotoxic N CO H Cl 2 pb – Mwt 253.7 S ur – PSA 78.4 A˚ 2 log P 3.11

1/ S t 2 4h V – FENTIAZAC CO2H F –CL8.6Antiinﬂammatory N pb 99.1% Mwt 329.8 Metabolism: 4-hydroxylation of ur – PSA 78.4 A˚ 2 Ph Cl log P 5.05

1/ t 2 6–12 h V – LONAZOLAC CO H N 2 F –CL– Antiinﬂammatory N pb 99% Mwt 312.8 Metabolism: aromatic ur 2% PSA 50.2 A˚ 2 4-hydroxylation, then sulfation Cl log P 4.13

t1/ 17±1h V – PIRAZOLAC N CO H 2 F N 2 F 100% CL 0.25±0.32 Antiinﬂammatory pb 99% Mwt 330.7 Metabolism: glucuronidation ur 10% PSA 55.1 A˚ 2 Cl log P 3.84

1/ MeO t 2 3.3 h V – TEPOXALIN F CL – Antiinﬂammatory > 1/ pb 98% Mwt 385.8 Metabolite: carboxylic acid (t 2 ur – PSA 67.6 A˚ 2 12–14 h) N N log P 3.16 N OH Cl O

1/ ± t 2 2.8 0.8 h V – ISOFEZOLAC F –CL– Antiinﬂammatory pb 99% Mwt 354.4 N ur 14±5% PSA 55.1 A˚ 2 N log P 3.56

CO2H

1/ t 2 9–11 h V – LICOFELONE F High CL – Antiinﬂammatory pb – Mwt 379.9 Metabolism: methyl and phenyl ur – PSA 37.3 A˚ 2 hydroxylation, glucuronidation N log P 6.73 Cl CO2H 505

1/ F t 2 17 h V 1.1 LAROPIPRANT F 71% CL – Prostaglandin (DP1) antagonist, pb >99% Mwt 435.9 vasoconstrictor, in combination ur 5% PSA 84.8 A˚ 2 with niacin as antilipemic S log P 3.82 Metabolism: glucuronidation O O N

Cl CO2H

1/ t 2 20–25 h V 6 ATRASENTAN N F – CL 3–7 Antineoplastic pb 99% Mwt 510.6 Metabolism: glucuronidation, N O O ur <0.1% PSA 88.5 A˚ 2 N-debutylation, O-demethylation log P 5.80 O OMe CO2H

1/ SPh t 2 61–90 h V – TANOMASTAT, BAY-129566 O F –CL– Matrix metalloproteinase pb 99.99% Mwt 410.9 inhibitor, antineoplastic CO H 2 ur – PSA 79.7 A˚ 2 log P 6.51

t1/ 8.1±4.3 h V – VADIMEZAN, ASA404, CO H 2 2 F 73%∗ CL – DMXAA ∗ O pb 99% Mwt 282.3 mice ur – PSA 63.6 A˚ 2 Antineoplastic O log P 3.60 Metabolism: glucuronidation

1/ ± t 2 29 9h V 0.20–0.25 FENCLOFENAC CO2H F 100% CL – Antiinﬂammatory O pb – Mwt 297.1 Cl ur – PSA 46.5 A˚ 2 log P 4.59

1/ ± ± t 2 1.1 0.2 h V 0.17 0.11 DICLOFENAC CO2H F 54±2% CL 4.2±0.9 Antiinﬂammatory pb >99.5% Mwt 296.2 Metabolized by CYP2C9 to NH ur <1% PSA 49.3 A˚ 2 4-hydroxy (t1/ 4.3 h); further Cl Cl 2 log P 4.55 metabolism: aromatic 5- and 3-hydroxylation, then 4-O-methylation (continued overleaf ) 506 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

t1/ 4.9±1.4 h V 0.36 ACECLOFENAC O CO2H 2 F –CL– Antiinﬂammatory O pb >99% Mwt 354.2 NH Metabolism: ester hydrolysis, ur <1% PSA 75.6 A˚ 2 aromatic 4-hydroxylation of Cl Cl log P 3.81 dichlorophenyl, then conjugation

1/ t 2 4–7 h V 0.14 LUMIRACOXIB CO2H F 74% CL 2.1 Antiinﬂammatory pb 98% Mwt 293.7 Metabolism: oxidation of CH3 to NH 2 ur 3.3% PSA 49.3 A˚ CO2H, 4 -hydroxylation of Cl F log P 3.90 dihaloarene, then glucuronidation; withdrawn in 2007 because of hepatotoxicity

1/ ± CO H t 2 3 1h V 0.14–0.67 MECLOFENAMIC ACID 2 ∗ F 65±3% CL 3.2 ∗sheep NH pb 99.8% Mwt 296.2 Antiinﬂammatory ur 3±1% PSA 49.3 A˚ 2 Metabolism: glucuronidation, Cl Cl log P 5.44 oxidation of CH3 to CH2OH, then to CO2H

t1/ 2.5±0.6 h V 0.16 TOLFENAMIC ACID CO2H 2 F 60% CL 2.4±0.2 Antiinﬂammatory pb 99.7% Mwt 261.7 Metabolism, aromatic NH ur <8% PSA 49.3 A˚ 2 hydroxylation (ortho to Cl), log P 5.47 oxidation of CH3 to CHO

t1/ 1.5±0.1 h V 0.11 CLONIXIN CO2H 2 F –CL– Analgesic pb – Mwt 262.7 Metabolism: aromatic 4-(ortho N NH ur – PSA 62.2 A˚ 2 to Cl)- and 5-hydroxylation, log P 4.71 hydroxylation of CH3

t1/ 3±1h V 1.1 MEFENAMIC ACID CO2H 2 F Low CL 5.4 Antiinﬂammatory pb 99% Mwt 241.3 NH Metabolism (by CYP2C9) to ur <6% PSA 49.3 A˚ 2 3-hydroxymethyl mefenamic log P 4.83 acid, then to 3-carboxymefenamic acid 507

t1/ 9h V – FLUFENAMIC ACID CO2H 2 F – CL 1.2–2.3 Antiinﬂammatory > NH pb 90% Mwt 281.2 Prodrug: etofenamate ur <1% PSA 49.3 A˚ 2 (monoester of diethyleneglycol) log P 5.22 for topical application

CF3

1/ CO2H t 2 2h V 0.12 NIFLUMIC ACID F –CL0.7Antiinﬂammatory N NH pb 90–97% Mwt 282.2 Metabolism: glucuronidation, ur 5% PSA 62.2 A˚ 2 aromatic 4- and 5-hydroxylation, log P 4.46 then sulfation and glucuronidation CF3

t1/ 4–9 h V/F 0.09 TRANILAST CO2H 2 F 0.2%∗ CL/F 0.13 ∗transdermal NH pb – Mwt 327.3 Antiallergic ˚ 2 MeO ur – PSA 84.9 A Metabolism: glucuronidation, O log P 3.17 4-O-demethylation MeO

1/ ± O t 2 3.5 1.1 h V – AMLEXANOX F –CL– Antiallergic, antiasthmatic CO2H pb – Mwt 298.3 Metabolism: hydroxylation of ur 17% PSA 103 A˚ 2 O N NH CHMe2, then conjugation 2 log P 3.74

t1/ 2.5 h (iv) V 0.25 CB 10-277 CO H 2 2 F –CL1.3Antineoplastic N pb – Mwt 193.2 N N ur – PSA 65.3 A˚ 2 log P 2.59

1/ ± t 2 4–12 h V 0.17 0.03 PROBENECID F 100% CL 0.4 Uricosuric CO H 2 pb 90±5% Mwt 285.4 Metabolism: acyl N ur 1.2±0.2% PSA 83.1 A˚ 2 glucuronidation, hydroxylation S log P 2.51 at CH Me and Me, O O 2 N-depropylation, oxidation of CH3 to CO2H

1/ N t 2 2–3 h V 0.26 AZOSEMIDE O O HN N F 15–20% CL 1.7 Diuretic S N > H2N pb 95% Mwt 370.8 Metabolism: N-dealkylation ur 27% PSA 163 A˚ 2 Cl N S H log P 1.40

(continued overleaf ) 508 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ ± O O t 2 0.3–3.4 h V 0.11 0.02 FUROSEMIDE F 61±17% CL 2.0±0.4 S CO2H Diuretic H2N pb 98.8±0.2% Mwt 330.7 Metabolism: acyl ± ˚ 2 Cl N O ur 66 7% PSA 131 A glucuronidation, N-dealkylation H log P 2.30

1/ ± ± O O t 2 0.8 0.2 h V 0.13 0.03 BUMETANIDE S CO H F 59–89% CL 2.6±0.5 Diuretic H N 2 2 pb 99% Mwt 364.4 Metabolism: glucuronidation, β-, ± ˚ 2 γ δ O ur 62 20% PSA 127 A -, and -hydroxylation of butyl, log P 2.88 HN N-debutylation, oxidation of CH3 to CO2H

1/ ± O O t 2 1.0 0.5 h V 0.25–0.30 PIRETANIDE S CO H F 80% CL 3.8±0.8 (iv) Diuretic H N 2 2 pb 94% Mwt 362.4 Metabolism: cleavage of ˚ 2 O ur 50% PSA 118 A pyrrolidine to aminobutanol log P 2.30 N

1/ HO O O t 2 1.6 h (iv) V 0.14 FLUORESCEIN F –CL1.3Diagnostic aid pb 85–90% Mwt 332.3 Metabolism: glucuronidation ur – PSA 76.0 A˚ 2 CO H 2 log P 2.68

t1/ 8–16 h V 0.2 DEFERASIROX, ICL 670 CO2H 2 F 74±13% CL 0.9±0.2 Iron chelator N N pb 99% Mwt 373.4 Metabolism: glucuronidation ur 2% PSA 108 A˚ 2 N log P 5.15 OH HO

t1/ 3–6 h V –ATALUREN F O N 2 F High CL – Nonsense mutation suppressor CO2H N pb – Mwt 284.2 for treatment of cystic ﬁbrosis ur – PSA 76.2 A˚ 2 and muscular dystrophy log P 3.73

1/ S t 2 24 h V 0.18 TETOMILAST, OPC-6535 F 100% CL – PDE4 inhibitor EtO N CO2H N pb >99.5% Mwt 370.4 ur – PSA 110 A˚ 2 EtO log P 3.48 509

1/ t 2 3.2 h (iv) V 0.3 TEZOSENTAN OH F – CL 8–9 Endothelin antagonist for MeO O pb >99% Mwt 605.6 treatment of heart failure O N ur 2% (iv) PSA 208 A˚ 2 Metabolism: hydroxylation at O O N N N N S log P 0.88 CHMe2 N N N H H N

t1/ 195±95 h V 0.3 TUCARESOL O CO2H 2 F –CL0.03Antisickling agent, increases HO O pb >98.5% Mwt 272.3 oxygen afﬁnity of hemoglobin ur – PSA 83.8 A˚ 2 log P 2.75

1/ t 2 7h V 1 BEXAROTENE CO2H F 8% (dog) CL – Antineoplastic pb >99% Mwt 348.5 Metabolism: hydroxylation of 2 ur <1% PSA 37.3 A˚ CH2CH2, then oxidation of log P 6.90 alcohol to ketone

1/ CO2H t 2 3–5 h V – TAMIBAROTENE H F –CL– Retinoic acid-α agonist, N pb >99% Mwt 351.4 antileukemic ˚ 2 O ur – PSA 66.4 A Metabolism: oxidation of CH2 to log P 5.52 ketone

1/ CO2H t 2 6–8 h V 0.7–0.9 TAC-101 O ∗ ∗ F 62–94% CL 1.3 rat, dog Me3Si N pb – Mwt 385.6 Retinoic acid analog, H ur – PSA 66.4 A˚ 2 antineoplastic log P 7.73 SiMe3

1/ ∗ ∗ CO2Et t 2 14–20 h V 2 TAZAROTENE ∗∗ ∗ F 1–5% CL 1.6 ∗acid on oral dosing of ester ∗∗ N pb 99% Mwt 351.5 from topical dosing ur 0% PSA 64.5 A˚ 2 Topical antipsoriatic log P 5.99 Metabolism: ester hydrolysis, S oxidation to sulfoxide

1/ O t 2 1.7–9.3 h V/F 1.53 PRANLUKAST F <20% CL/F 19 Antiasthmatic N NH N > N pb 99% Mwt 481.5 Metabolism: phenyl O ˚ 2 O N ur Low PSA 119 A 4-hydroxylation, then H log P 4.20 O-sulfation, benzylic hydroxylation, then oxidation to Ph O ketone

(continued overleaf ) 510 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ ∗ O t 2 6–10 h V – REPIRINAST F 5–80%∗ CL – ∗acid on oral dosing of ester O O pb 97%∗ Mwt 355.4 Antiallergic ∗ HN ur 7.4% PSA 81.7 A˚ 2 Ester not detectable in plasma log P 4.89 on oral dosing O O

1/ t 2 1.1–3.3 h V 0.43 NEDOCROMIL F 2–3%∗ CL 10.2 ∗pulmonal: 6% HO C N O CO H 2 2 pb 89% Mwt 371.3 Antiallergic, antiasthmatic ur 64–81% PSA 121 A˚ 2 log P 1.30 O O

t1/ 1.0–1.5 h V 0.32 CROMOGLICIC ACID, HO C O O CO H 2 2 2 F 1–2% CL 8 CROMOLYN pb 57–69% Mwt 468.4 Antiasthmatic, antiallergic OH ur 50% PSA 166 A˚ 2 O O O O log P 2.00

1/ t 2 1.4–1.6 h V 0.5 ACIFRAN O CO2H F –CL2.6Antihyperlipoproteinemic pb 88% Mwt 218.2 ˚ 2 O ur 78–95% PSA 63.6 A log P 2.04

1/ t 2 2h V –FUREGRELATE ∗ F 75–80% CL – ∗dog N O pb – Mwt 253.3 Thromboxane A2 synthase CO2H ur 62–78% PSA 63.3 A˚ 2 inhibitor log P 2.76

1/ t 2 5–8 h V 0.8 FEBUXOSTAT N F 84% CL 2.6–3.1 Xanthine oxidase inhibitor for CO2H pb 99.2% Mwt 316.4 treatment of gout NC S ur 3% PSA 111 A˚ 2 Metabolism: oxidation of log P 4.87 isobutyl, hydroxylation, O glucuronidation

1/ t 2 0.5–1.0 h V 0.3–0.9 REPAGLINIDE F 56–63% CL 7.8 Antidiabetic CO2H O pb >98% Mwt 452.6 Metabolism: glucuronidation, ur <2% PSA 78.9 A˚ 2 piperidine 3-hydroxylation, N O H log P 4.69 O-deethylation, 2-hydroxylation N of isopropyl, piperidine cleavage to 5-aminovaleric acid, then aniline N-dealkylation 511

1/ t 2 8–16 h V/F 1.1 ZAFIRLUKAST O O O F –CL/F 5.1 Antiasthmatic, leukotriene D4 MeO S pb >99% Mwt 575.7 and E antagonist, CYP2C9 N 4 H ur <10% PSA 124 A˚ 2 substrate, and inhibitor O log P 5.04 Metabolism (animals): O N-demethylation, hydrolysis of HN carbamate, then N-acetylation of N aniline, hydroxylation of cyclopentyl group

Table 68.2 Salicylic acid analogs. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

t1/ <6h V – BENZOIC ACID CO H 2 2 F 100% CL – Metabolite: hippuric acid pb – Mwt 122.1 (N-benzoylglycine), benzoyl ur – PSA 37.3 A˚ 2 glucuronide log P 1.56

1/ ∗ ± t 2 2.4 h V 0.17 0.03 SALICYLIC ACID F 100% CL 0.18–0.88 ∗300 mg CO2H OH pb 80–95% Mwt 138.1 Metabolism: aromatic ur 2–30% PSA 57.5 A˚ 2 5-hydroxylation (to gentisic log P 2.01 acid), conjugation with glucuronic acid and glycine

1/ CO2H t 2 34 h V 0.13 2-HYDROXY-4- OH F –CL0.4TRIFLUOROMETHYL pb >99% Mwt 206.1 BENZOIC ACID ur – PSA 57.5 A˚ 2 Main metabolite of triﬂusal log P 4.25 CF3

t1/ 1.5±1.0 h V 0.26–0.33 MESALAZINE CO2H 2 OH F 15–25% CL 4–9 5-AMINOSALICYLIC ACID pb 43–60% Mwt 153.1 Metabolism: N-acetylation ur <1% PSA 83.6 A˚ 2 H N 2 log P 0.74 (continued overleaf ) 512 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDs)

1/ t 2 1.0–1.5 h V – SALICYLAMIDE O NH2 F <10% CL – Main metabolites: pb – Mwt 137.1 O-glucuronide, O-sulfate, OH ur <2% PSA 63.3 A˚ 2 gentisamide (2,5- log P 1.35 dihydroxybenzamide); no hydrolysis to salicylic acid

1/ ± ∗ t 2 0.9 0.2 h V – SALICYLAMIDE O-ACETIC O NH 2 F –CL– ACID; (2-CARBAMOYL- pb – Mwt 195.2 PHENOXY) ACETIC ACID O CO2H ur – PSA 89.6 A˚ 2 ∗im log P −0.61 Analgesic Metabolite: salicylamide

t1/ 0.25 h V 0.15±0.03 ACETYLSALICYLIC ACID, CO H 2 2 F 68±3% CL 9.3±1.1 ASPIRIN O 1/ pb 49% Mwt 180.2 Deacetylation: t 2 2h ± 2 O ur 1.4 1.2% PSA 63.6 A˚ Deacetylation of esters of 1/ log P 1.40 acetylsalicylic acid: t 2 1–3 min

t1/ 0.5 h V 0.5 TRIFLUSAL CO2H 2 O F – CL 10.8 Metabolism: deacetylation to pb – Mwt 248.2 2-hydroxy-4-triﬂuoromethyl- O ur – PSA 63.6 A˚ 2 benzoic acid log P 2.90 (see above) CF3

1/ CO H t 2 1h V 0.07 OLSALAZINE, MORDANT 2 < OH F 5% CL 1.2 YELLOW pb 99% Mwt 302.2 Metabolite: N ur <1% PSA 140 A˚ 2 5-Aminosalicylic acid N 1/ ± log P 3.57 (t 2 1.5 1.0 h) HO

CO2H

1/ CO H t 2 1.4–14 h V 7.5 SULFASALAZINE 2 < OH F 20% CL 0.26 Cleaved in the colon by gut pb 95–99% Mwt 398.4 bacteria to sulfapyridine and N N ur 10–15% PSA 150 A˚ 2 5-aminosalicylic acid N log P 3.05 HN S O O

1/ CO H t 2 2–3 h V –BALSALAZIDE 2 < ∗ OH F 1% CL 1.2 10% N-acetyl-5-aminosalicylic CO2H pb >99% Mwt 357.3 acid; cleaved by gut bacteria to ∗ N ur <1% PSA 149 A˚ 2 5-aminosalicylic acid N log P 3.11 HN

O 513

1/ SO3H t 2 18 h V – SULTOSILIC ACID > OH F 60% CL – Antihyperlipidemic O O pb – Mwt 344.4 Metabolism: hydroxylation and S ur 28% PSA 135 A˚ 2 O oxidation of CH3 to CO2H log P 0.75

t1/ 11±2h V 0.10±0.01 DIFLUNISAL CO2H 2 ± OH F 90% CL 0.10 0.02 Analgesic, antiinﬂammatory F pb 99.9% Mwt 250.2 Metabolism: sulfation, phenolic ur 6±3% PSA 57.5 A˚ 2 and acyl glucuronidation (acyl 1/ log P 3.65 glucuronide t 2 12–30 h) F

t1/ 2h V –FENDOSAL CO2H 2 OH F –CL– Analgesic, antiinﬂammatory pb – Mwt 381.4 Metabolism: hydroxylation ur – PSA 62.5 A˚ 2 N log P 5.04

1/ ∗ O t 2 4–8 h V – DIACEREIN, DIACETYLRHEIN F 35%∗ CL – ∗Rheinonoraldosingof CO H 2 pb 99%∗ Mwt 368.3 diacerein ur 20%∗ PSA 124 A˚ 2 Antiarthritic log P 3.13 Metabolism: deacetylation to O O O rhein, then glucuronidation, O O sulfation 514

69 Quinolonecarboxylic Acids (Gyrase Inhibitors)

Nalidixic acid was introduced in 1963 as an antibacterial for the treatment of urinary tract infections. Despite belonging to a new class of antibacterial agents, nalidixic acid was no great success, mainly because of its low potency, its side effect profile, and the quick development of resistance. As reflected by its low volume of distribution and high affinity to plasma proteins, nalidixic acid does not reach high concentrations in most organs and is therefore of little therapeutic value. These issues were addressed by Japanese and German researchers, who introduced a basic, positively charged group to enhance the solubility and volume of distribution, while lowering the affinity to plasma proteins. Thereby, the drug concentration in potentially infected tissues was increased and the interindividual variability of pharmacokinetic (PK) parameters reduced. These efforts led to compounds such as pipemidic acid (1974), norfloxacin (1978), pefloxacin (1979), ofloxacin (1982), and ciprofloxacin (1983) (Scheme 69.1).

O O O

CO2H F CO2H F CO2H

N N N N N N HN HN

Nalidixic acid Norfloxacin Ciprofloxacin − t1/2 1 8 h, F 96% t1/2 5 h, F 35% t1/2 4 h, F 60% pb 93−97%, V 0.5−0.6 l kg−1 pb 15−20%, V 3.2 l kg−1 pb 40%, V 1.8 l kg−1

Scheme 69.1 Quinolone antibacterials.

Quinolone antibiotics are potent inhibitors of bacterial DNA gyrase, but much less potent inhibitors of eukaryotic type II topoisomerase. DNA gyrase is an enzyme capable of temporarily breaking DNA and then reassembling it. This enzyme belongs to the topoisomerases and is essential for the replication, transcription, recombination, and reparation of DNA, as well as for the compact packing of DNA within cells. The newer quinolone antibiotics (Table 69.1) are mainly metabolized at the alkylamine substructures by oxidative N-dealkylation and conjugation.

Table 69.1 Quinolonecarboxylic acids and related compounds. V inlkg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ O t 2 6–7 h V – OXOLINIC ACID F 50% CL – Antibacterial O CO2H pb 77–85% Mwt 261.2 Metabolism: acetal hydrolysis, then ˚ 2 O N ur 5% PSA 76.1 A O-methylation by COMT log P −0.38

1/ O t 2 1–2 h V 0.33 CINOXACIN F 60–85% CL 2.5 O CO2H Antibacterial pb 43–63% Mwt 262.2 N ˚ 2 O N ur 60–85% PSA 88.4 A log P 0.49

1/ O N N t 2 4.5 h V – PEMIROLAST N F –CL–Antiallergic N N pb – Mwt 228.2 H ur 10–15% PSA 87.1 A˚ 2 N log P 0.22

1/ . ± . O O t 2 1 7 0 5h V 0.8 FLOSEQUINAN S F 72% CL 8.2 Antihypertensive 1/ pb – Mwt 239.3 Metabolite: sulfone (t 2 30–40 h); ˚ 2 F N ur 1% PSA 56.6 A withdrawn in 1993 because of log P −1.43 excessive toxicity

1/ . ∗ O t 2 7h V 1 4 FLUMEQUINE F 56–93%∗ CL – ∗calves F CO2H pb 75%∗ Mwt 261.3 Antibacterial ˚ 2 N ur – PSA 57.6 A Metabolism: benzylic log P 0.88 hydroxylation, glucuronidation

1/ ± . ± . O t 2 5 1h V 0 64 0 05 ROSOXACIN F >64% CL 2.1±0.2 CO2H Antibacterial pb 70% Mwt 294.3 Metabolism: pyridine N-oxidation, ˚ 2 N ur 4–5% PSA 70.5 A glucuronidation N log P 0.57

1/ O O t 2 1.1–3.3 h V 0.43 NEDOCROMIL ∗ F 2–3% CL 10.2 ∗pulmonal: 6% pb 89% Mwt 371.3 Antiallergic, antiasthmatic ur 64–81% PSA 121 A˚ 2 HO2C O N CO2H log P 1.30

(continued overleaf ) 516 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)

1/ F O t 2 4–9 h V – ELVITEGRAVIR F –CL– Cl CO2H HIV-1 integrase inhibitor, antiviral pb – Mwt 447.9 Metabolism: glucuronidation ˚ 2 O N ur – PSA 87.1 A OH log P 3.26

1/ O t 2 1–8 h V 0.5–0.6 NALIDIXIC ACID F 96% CL – Antibacterial CO2H pb 93–97% Mwt 232.2 Metabolites: acyl glucuronide, ˚ 2 1/ N N ur 11–33% PSA 70.5 A 7-hydroxymethyl (t 2 3–6 h, pb log P 0.03 63%), 7-carboxy

1/ O t 2 12 h V – AMFONELIC ACID F –CL– CO2H Dopamine reuptake inhibitor, pb – Mwt 308.3 locomotor stimulant 2 N N ur – PSA 70.5 A˚ log P 1.38

1/ O t 2 6–24 h V 4 VORELOXIN F –CL10Antineoplastic, topoisomerase II CO2H pb 50–75% Mwt 401.4 inhibitor ˚ 2 N N N ur – PSA 136 A Metabolism: O-demethylation, N log P −0.86 glucuronidation, N-dealkylation H SN MeO

1/ . ± . O t 2 3 5 0 2h V 1.5–7.3 TOSUFLOXACIN

F CO2H F – CL 6.4–39 Antibacterial, racemate pb 37% Mwt 404.3 Metabolism: glucuronidation, ± ˚ 2 N N N ur 34 9% PSA 99.8 A replacement of NH2 by OH H N 2 F log P 1.01

1/ ± O t 2 11 1h V 1.3 TROVAFLOXACIN F 90% CL 1.4 Metabolism: acyl glucuronidation, F CO2H pb 76–88% Mwt 416.4 N-sulfation, N-acetylation . ± . 2 H N N N ur 9 3 2 5% PSA 99.8 A˚ Prodrug: alatroﬂoxacin F log P 1.08 (Chapter 33); withdrawn in 2001 H N because of hepatotoxicity 2 H

F 69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 517

1/ . ± . O t 2 8 0 0 5h V 1.5 TEMAFLOXACIN F 90% CL 3.4 Metabolism: oxidative degradation F CO2H pb 26% Mwt 417.4 of piperazine to ethylenediamines; ± ˚ 2 N N ur 74 18% PSA 72.9 A withdrawn in 1992 because of HN F log P 1.28 excessive toxicity (hemolytic uremic anemia)

1/ O t 2 21–29 h V 1.4–1.5 DIFLOXACIN F –CL–Antibacterial, does not cross bbb F CO2H pb – Mwt 399.4 Metabolism: N-demethylation, ˚ 2 N N ur 10% PSA 64.1 A N-oxidation, oxidative degradation N log P 0.84 of piperazine to ethylenediamines

1/ . ± . . ± . O t 2 4 1 0 9h V 1 8 0 4 CIPROFLOXACIN F 60±12% CL 6.0±1.2 Antibacterial, does not cross bbb F CO2H pb 40% Mwt 331.3 Metabolism: piperazine ± ˚ 2 N N ur 65 12% PSA 72.9 A 3 -hydroxylation, N-sulfation HN log P 1.31

1/ ± O t 2 11 1h V 5–8 GREPAFLOXACIN F 72% CL 3.9±0.9 Metabolism: glucuronidation, F CO2H pb 50% Mwt 359.4 N-sulfation, oxidative degradation ± ˚ 2 N N ur 9 3% PSA 72.9 A of piperazine; withdrawn in 1999 HN log P 2.27 because of QT interval prolongation

1/ . ± . . ± . O t 2 4 5 1 0h V 1 6 0 4 ENOXACIN ± . ± . F CO2H F 87 16% CL 5 0 1 2 Antibacterial, does not cross bbb pb 40% Mwt 320.3 Metabolism: N-acetylation, ± 2 N N N ur 45 11% PSA 85.8 A˚ 3 -oxidation of piperazine to lactam, HN log P 1.21 oxidative degradation of piperazine

1/ . ± . / . ± . O t 2 5 0 0 7h V F 3 2 1 4 NORFLOXACIN ± . ± . Antibacterial F CO2H F 35 5% CL/F 7 2 3 0 pb 15–20% Mwt 319.3 Metabolism: N-formylation, ± 2 N N ur 29 3% PSA 72.9 A˚ N-acetylation, 3 -oxidation of HN log P 1.74 piperazine to lactam, cleavage of piperazine to N-2-(aminoethyl)aniline and an unsubstituted aromatic amine (continued overleaf ) 518 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)

1/ ± O t 2 10 1h V 1.5 PEFLOXACIN F 100% CL 2.1 Metabolism: glucuronidation, F CO2H pb 20–30% Mwt 333.4 N-demethylation, 3-oxidation to ur 42% PSA 64.1 A˚ 2 N N lactam, N-oxidation log P 1.92 N

1/ . ± . . ± . O t 2 3 4 0 2h V 1 9 0 2 PIPEMIDIC ACID F 93±11% CL 6.3±0.5 Antibacterial CO2H N pb 10–30% Mwt 303.3 Metabolism: N-acetylation, ur 90% PSA 98.7 A˚ 2 N-formylation, 3-oxidation of N N N log P −0.19 piperazine to lactam HN

1/ ± O t 2 38 3h V 2.0–2.1 RUFLOXACIN F 70%∗ CL 0.62 ∗monkey F CO2H pb 60% Mwt 363.4 Antibacterial ur 30–50% PSA 89.4 A˚ 2 Metabolism: N-demethylation, N N log P 1.85 oxidation to sulfoxide N S

1/ . ± . . ± . O t 2 8 0 1 4h V 2 3 0 3 LOMEFLOXACIN F 97±2% CL 3.3±0.5 Antibacterial, racemate F CO2H pb 10–20% Mwt 351.4 Metabolism: glucuronidation ur 65±9% PSA 72.9 A˚ 2 N N log P 2.46 HN F

1/ ± . ± . O t 2 11 2h V 1 5 0 3FLEROXACIN F >98% CL 2.4 Antibacterial, does not cross bbb F CO2H pb 25±5% Mwt 369.3 Metabolism: N-demethylation, ur 60–70% PSA 64.1 A˚ 2 N N N-oxidation log P 1.84 N F F

1/ . ± . . ± . O t 2 6 5 1 5h V 2 2 0 2 GATIFLOXACIN F 96% CL 3.3±0.5 F CO2H Antibacterial pb 20% Mwt 375.4 Metabolism: oxidative degradation ˚ 2 N N ur 82–88% PSA 82.1 A of piperazine HN OMe log P 2.10

1/ . ± . . ± . O t 2 5 7 1 0h V 1 8 0 3 OFLOXACIN F 100% CL 3.5±0.7 F CO2H Antibacterial pb 25±6% Mwt 361.4 Metabolism: N-demethylation, ± ˚ 2 N N ur 64 16% PSA 73.3 A N-oxidation N O log P 1.86 69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 519

1/ ± O t 2 7 1h V 1.3 LEVOFLOXACIN F 99% CL – Antibacterial F CO2H pb 24–52% Mwt 361.4 Does not racemize in vivo ur >85% PSA 73.3 A˚ 2 Metabolites: N-desmethyl, N-oxide N N log P 1.86 N O

1/ ± t 2 4 2h V 0.9 PAZUFLOXACIN O F –CL6.8Parenteral antibacterial F CO2H pb – Mwt 318.3 Metabolism: glucuronidation, ur 70% PSA 92.9 A˚ 2 oxidative degradation of N log P 0.35 aminocyclopropyl group (to 1-hydroxyethyl, NH2 O 3-hydroxypropanoyl)

1/ O t 2 12 h V 2.0–3.6 MOXIFLOXACIN F 90% CL 3.3±0.5 Antibacterial F CO2H pb 39–52% Mwt 401.4 Metabolism: acyl glucuronidation, H ur 20±5% PSA 82.1 A˚ 2 N-sulfation N N HN log P 1.90 OMe H

1/ O t 2 9–16 h V 3.4–5.3 NEMONOXACIN F –CL3.7 CO2H Antibacterial pb 16% Mwt 371.4 H N ur 34–56% PSA 96.1 A˚ 2 2 N N log P 0.94 OMe

1/ ± / O t 2 11 4h V F 0.7 BALOFLOXACIN F 88%∗ CL 3.0±0.5 ∗dog F CO2H H pb – Mwt 389.4 Antibacterial N ur 23%∗ PSA 82.1 A˚ 2 Metabolism: acyl glucuronidation, N N log P 1.54 N-demethylation OMe

1/ O t 2 7h V – BESIFLOXACIN F –CL–∗animals F CO2H H2N pb 39–44% Mwt 393.8 Topical and ophthalmic ur 23%∗ PSA 86.9 A˚ 2 N N antibacterial log P 2.57 Cl

(continued overleaf ) 520 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)

1/ . ± . . ± . O t 2 5 7 0 7h V 2 6 0 3 CLINAFLOXACIN F 90% CL 5.3±0.6 F CO2H Antibacterial pb 50–60% Mwt 365.8 ± ˚ 2 N N ur 58 18% PSA 86.9 A H N log P 2.45 2 Cl

1/ . ± . O t 2 5 9 0 7h V 2.8 SITAFLOXACIN F 89% CL 4.6 Antibacterial F CO H 2 pb 49% Mwt 409.8 Metabolism: N-acetylation, ur 26–86% PSA 86.9 A˚ 2 replacement of NH by OH, then N N 2 H N log P 1.53 oxidation to ketone, ring scission of 2 Cl pyrrolidine to aminobutanol, then F oxidation to aminobutyric acid

1/ . ± . O t 2 7 3 2 5h V 1.5–3.5 GEMIFLOXACIN F 71% CL 12.5±5.6 Antibacterial F CO2H pb 60–70% Mwt 389.4 Metabolism: glucuronidation, H N ± ˚ 2 2 N N N ur 18 4% PSA 121 A N-acetylation, isomerization of log P 1.04 oxime

MeO N

1/ ± NH2 O t 2 18 2h V 4–6 SPARFLOXACIN F 90% CL 2.7 Antibacterial F CO2H pb 45% Mwt 392.4 Metabolism: acyl glucuronidation ur 9–10% PSA 98.9 A˚ 2 N N log P 2.60 HN F

1/ ∗ t 2 10–12 h V 19 ULIFLOXACIN ∗ O F –CL– ulifloxacin on oral dosing of pb 41–59% Mwt 349.4 prulifloxacin (Chapter 23) F CO2H ur – PSA 98.2 A˚ 2 Metabolism: acyl glucuronidation, log P 2.53 oxidative cleavage of piperazine N N S Prodrug: prulifloxacin, which HN cannot be detected in plasma after oral dosing 69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 521

1/ . ∗ O t 2 13–18 h V 1.0–1 5 GARENOXACIN ∗ F 76%∗ CL – monkey CO2H pb 87% Mwt 426.4 Antibacterial ˚ 2 Metabolism: glucuronidation, N ur 30–50% PSA 78.9 A HN sulfation, probably forms reactive O log P 1.62 metabolite (isoindole) by oxidation F F of isoindoline

t1/ 4h V – CINCHOPHEN CO2H 2 F High CL – Analgesic, induces ulcers, pb – Mwt 249.3 hepatotoxic ur <5% PSA 50.2 A˚ 2 Metabolism: aromatic N log P 4.18 hydroxylation

1/ . ± . CO2H t 2 13–18 h V 0 24 0 08 BREQUINAR . ± . ∗ F F High CL 0 5 0 2 iv pb >98% Mwt 375.4 Immunosuppressant ur 0.1–6%∗ PSA 50.2 A˚ 2 F N log P 6.69

70 β-Lactams

In 1928, Alexander Fleming, a microbiologist working at St. Mary’s Hospital in London, discovered a mold (Penicillium notatum), which inhibited bacterial growth in its proximity. He called the antibiotic penicillin and explored its usefulness as topical antiseptic, but failed to test its efficacy after parenteral dosing in vivo. More than a decade later, Florey, Chain, and Abraham at Oxford University administered penicillin broth parenterally to mice infected with Streptococci, and later to patients, with remarkable success. The production of penicillin broth, containing about 10% penicillin, was scaled up significantly in the United Kingdom and United States to meet the requirements of the Allied Forces during the war. Pure, crystalline penicillin was obtained by Oskar Wintersteiner in 1943, who found that several different penicillins were produced by the mold, including 2-pentenylpenicillin (penicillin F) and benzylpenicillin (penicillin G) (Scheme 70.1). X-ray structural analysis by Hodkin in 1945 confirmed the β-lactam structure, and the total synthesis of phenoxymethylpenicillin was accomplished in 1957 by John C. Sheehan. This chemical synthesis was, however, more tedious and expensive than the fermentative route.

H H H H N S N S O N O N O O CO2H CO2H 2-Pentenylpenicillin Benzylpenicillin penicillin F penicillin G t1/2 30–40 min, F < 30%

H H H N H N O S 2 S O N N O O CO2H CO2H Phenoxymethylpenicillin 6-Aminopenicillamic acid penicillin V t1/2 0.5–1.0 h, F 40–60%

Scheme 70.1 Natural and synthetic penicillins.

Oral bioavailability of natural penicillins is poor, but side-chain variations quickly led to semisynthetic penicillins with improved pharmacokinetics (PK) (Table 70.1). While growing Penicillium notatum, the broth always contains 6-aminopenicillamic acid, which can be isolated and acylated with various acids to prepare other, unnatural penicillin analogs. The most remarkable property of β-lactam antibiotics is their low toxicity to humans. Even intravenous doses of several grams are tolerated. Because of their ability to acylate plasma proteins (e.g., albumin), however, β-lactam allergies occasionally result. Penicillins kill bacteria by acylating a bacterial transpeptidase involved in the formation of cell walls. Because of the massive use of β-lactam antibiotics in the past decades, resistance is emerging and posing a real threat to our ability to ﬁght bacterial infections [1]. Most penicillins undergo β-lactam hydrolysis in vivo to lose their antibiotic activity. Because of their hydrophilicity, β-lactams are not oxidized to sulfones but mainly excreted renally, either unchanged or as hydrolyzed β-lactam. Anumberofotherβ-lactams have been isolated, mainly from fungi, and used as leads for the development of antibiotics. These include the carbapenems, cephalosporins, and various β-lactamase inhibitors.

70.1 Cephalosporins

The biochemist Giuseppe Brotzu discovered the fungus Cephalosporium acremonium in 1945 in a sewer outlet near the Sardinian coast. This mold produces anumberofβ-lactam antibiotics that are weaker than penicillins but more resistant to bacterial penicillases. Of these, only cephalosporin C attained some therapeutic signiﬁcance (Scheme 70.2).

H H HO2C N S

NH2 O N O O CO2H O

Cephalosporin C Scheme 70.2

As in the case of penicillins, many synthetic cephalosporin analogs with improved PK and potency have been prepared by side-chain modiﬁcation of the natural cephalosporins (Table 70.2).

Reference

1. (a) Oelschlaeger, P., Ai, N., DuPrez, K.T., Welsh, W.J., and Toney, J.H. (2010) Evolving carbapenemases: can medicinal chemists advance one step ahead of the coming storm? 524 70 β-Lactams

J. Med. Chem., 53, 3013–3027; (b) Taubes, G. (2008) The bacteria ﬁght back. Science, 321, 356–361; (c) Walsh, C. and Wright, G. (2005) Antibiotic resistance. Chem. Rev., 105, 391–393; (d) Fisher, J.F., Meroueh, S.O., and Mobashery, S. (2005) Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity. Chem. Rev., 105, 395–424.

Table 70.1 Penicillins, carbapenems, and related compounds. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ . ± . . ± . H t 2 0 9 0 1h V 0 21 0 05 CLAVULANIC ACID O OH F 75±21% CL 3.6±1.0 β-Lactamase inhibitor N pb 22% Mwt 199.2 O ur 43±14% PSA 87.1 A˚ 2 CO2H log P −0.32

t1/ 1.0–1.7 h V 0.32 SULBACTAM H O O 2 S F – CL 3.7–5.1 β-Lactamase inhibitor pb 38% Mwt 233.2 N ˚ 2 O ur 75–85% PSA 100 A CO2H log P 0.39

1/ ∗ O t 2 0.7–1.2 h V 0.2–0.5 TAZOBACTAM H O ∗ S F 0% CL 3.1 iv N N pb 20–23% Mwt 300.3 β-Lactamase inhibitor N N ˚ 2 O ur 64% PSA 131 A CO2H log P 0.60

1/ HO t 2 0.9–1.3 h V – FAROPENEM H H F 20–30% CL – S O pb 90–95% Mwt 285.3 N ur 14–20% PSA 112 A˚ 2 O log P −1.09 CO2H

1/ ∗ H t 2 1.1 h V 0.26 DORIPENEM N ∗ HO F Low CL 4.1 iv H H NH pb 8% Mwt 420.5 Metabolism: β-lactam O ∗ S ur 79±6% PSA 196 A˚ 2 hydrolysis, then conjugation S O NH N 2 log P −3.65 with glycine and taurine O CO2H

1/ ∗ N t 2 1.1 h V 0.2 BIAPENEM ∗ N F –CL2.5 iv HO H H N pb 8% Mwt 351.4 ur 47–53%∗ PSA 99.6 A˚ 2 S − . N log P 4 12 O CO2H 525

1/ H O t 2 3.8 h (iv) V 0.12 ERTAPENEM N β HO F Low CL 0.45 Metabolism: -lactam H H NH pb 85–95% Mwt 475.5 hydrolysis ur 70–78% PSA 182 A˚ 2 S N log P −1.07 O HO2C CO2H

1/ H O t 2 1h(iv) V 0.3 MEROPENEM N HO F Low CL 3.9 H H N pb 13% Mwt 383.5 ur 65% (iv) PSA 135 A˚ 2 S N log P −1.23 O CO2H

1/ t 2 1h(iv) V 0.19 PANIPENEM HO N F –CL2.6 H H NH pb – Mwt 339.4 S ur 30% PSA 130 A˚ 2 N − . O log P 2 85 CO2H

1/ . ± . . ± . HO t 2 0 9 0 1h V 0 23 0 05 IMIPENEM H H N . ± . NH F Low CL 2 9 0 3 Values for simultaneous 2 < S pb 20% Mwt 2994. administration with cilastatin N ur 69±15% PSA 139 A˚ 2 O log P −2.78 CO2H

1/ ∗ . ∗ HO t 2 0.7 h V 0 25 RITIPENEM NH ∗ H H 2 F 37–42% CL – ∗acid (ritipenem) on oral S O pb – Mwt 288.3 dosing of ester; no ester can be O ∗ N ur 16% PSA 155 A˚ 2 detected in plasma O O log P −1.44 O O O

1/ O t 2 1.7 h (iv) V 0.23 TOMOPENEM N F –CL1.9 HO H H N pb 9% Mwt 537.6 ur 70% (iv) PSA 218 A˚ 2 S NH N log P −5.00 O CO H H N O 2 2 N H HN

(continued overleaf ) 526 70 β-Lactams

1/ t 2 1h V 0.3–0.4 AMDINOCILLIN H F Low CL 5–6 Prodrug: amdinocillin pivoxil N N S pb – Mwt 325.4 N ur 63% PSA 98.5 A˚ 2 O log P 2.33 CO2H

1/ t 2 0.5–0.8 h V – CYCLACILLIN H H F High CL 7 N S pb 18–30% Mwt 341.4 H2N O N ur 24–91% PSA 138 A˚ 2 O log P 1.21 CO2H

1/ . ± . . ± . NH2 t 2 1 7 0 3h V 0 21 0 03 AMOXICILLIN H H ± . ± . N S F 93 10% CL 2 6 0 4 Metabolism: lactam and pb 18% Mwt 365.4 thioaminal hydrolysis, O N ur 86±8% PSA 158 A˚ 2 formation of diketopiperazine HO O CO2H log P 0.88

NH t1/ 1.3±0.2h V 0.28±0.07 AMPICILLIN 2 H 2 H F 62±17% CL 1.7 N S Prodrug esters: lenampicillin pb 18±2% Mwt 349.4 (about 20% higher F), O N ur 82±10% PSA 113 A˚ 2 pivampicillin, talampicillin O − . CO2H log P 0 87

1/ . ± . . ± . t 2 1 0 0 2h V 0 35 0 09 NAFCILLIN O NH2 H H F 36% CL 7.5±1.9 N S pb 89–90% Mwt 414.5 O N ur 27±5% PSA 121 A˚ 2 O log P 2.60 CO2H

1/ N t 2 0.6–1.1 h V 0.4–0.5 AZIDOCILLIN 3 H H F 57–64% CL – Metabolism in animals: N S pb – Mwt 375.4 reduction of azide to amine O N ur 37–40% PSA 136.5 A˚ 2 (minor extent), β-lactam O CO2H log P 2.30 hydrolysis

1/ . ± . ∗ . ± . N t 2 1 2 0 2h V 0 19 0 03 APALCILLIN F –CL2.0±0.5 ∗iv O N pb 38% Mwt 521.5 ± ˚ 2 OH NH ur 18 3% PSA 187 A H H log P 3.67 N S O N O CO2H 527

1/ . ± . . ± . N t 2 0 9 0 1h V 0 18 0 03 PIPERACILLIN F Low CL 2.6±0.7 N O O pb 16–22% Mwt 517.6 O NH ur 71±14% PSA 182 A˚ 2 H H log P 1.00 N S O N O CO2H

1/ t 2 0.8–1.5 h V 0.26 AZLOCILLIN HN N O F Low CL 2.5 pb 28±6% Mwt 461.5 O NH ur 65±9% PSA 173 A˚ 2 H H N S log P 0.83 O N O CO2H

1/ . ± . . ± . O t 2 1 3 0 4h V 0 20 0 06 MEZLOCILLIN O S N F 0% CL 1.44 N O pb 29±13% Mwt 539.6 ur 45±6% PSA 207 A˚ 2 O NH H H log P 0.33 N S O N O CO2H

1/ H H t 2 30–40 min V 0.3–0.4 BENZYLPENICILLIN, N S F <30% CL 6.9 PENICILLIN G pb 45–65% Mwt 334.4 Diethylaminoethyl ester of O N ˚ 2 O ur – PSA 112 A benzylpenicillin: penethamate CO2H log P 1.92

1/ t 2 0.5–1.0 h V 0.73 PHENOXYMETHYL- H H F 40–60% CL PENICILLIN, N S O pb 55–78% Mwt 350.4 PENICILLIN V O N ur 20–40% PSA 121 A˚ 2 O log P 1.94 CO2H

1/ t 2 0.9 h (iv) V 0.30 PHENETHICILLIN H H F 86% CL 4.2 N O S pb 75% Mwt 364.4 O N ur 48% PSA 121 A˚ 2 O log P 2.29 CO2H

(continued overleaf ) 528 70 β-Lactams

1/ ∗ OMe t 2 0.6–0.9 h V 0.3–0.4 METHICILLIN ∗ H H F –CL6.1±1.3 iv N S pb 57% Mwt 380.4 ± ˚ 2 MeO O N ur 88 17% PSA 130 A O log P 1.02 CO2H

1/ . ± . . ± . O t 2 0 6 0 2h V 0 33 0 09 OXACILLIN N H H F 33% CL 6.1±1.7 N S pb 92.2±0.6% Mwt 401.4 O N ur 46±4% PSA 138 A˚ 2 O log P 2.55 CO2H

1/ . ± . . ± . O t 2 0 6 0 1h V 0 09 0 02 CLOXACILLIN N H H F 43±16% CL 2.2±0.5 N S . ± . Cl pb 94 6 0 6% Mwt 435.9 O N ur 75±14% PSA 138 A˚ 2 O log P 2.38 CO2H

1/ O t 2 53 min V 0.19 FLUCLOXACILLIN, N H H F 55% CL 2.4 FLOXACILLIN N S Cl pb 95% Mwt 453.9 O N ur 35–76% PSA 138 A˚ 2 F O log P 2.89 CO2H

1/ . ± . . ± . O t 2 0 7 0 1h V 0 09 0 02 DICLOXACILLIN N H H F 68±18% CL 1.6±0.3 N S pb 96% Mwt 470.3 Cl ± ˚ 2 O N ur 60 7% PSA 138 A Cl O log P 3.10 CO2H

t1/ 1.0–1.5 h V 0.18 CARBENICILLIN HO2C 2 H H F 30–40% CL 0.68–1.9 N S pb 48% Mwt 378.4 O N ur 80–99% PSA 149 A˚ 2 O log P 1.13 CO2H

1/ . ± . ∗ O t 2 1 2 0 2h V 0.15 SULBENICILLIN HO S O F Low CL 1.6 ∗iv H H pb 50% Mwt 414.5 N S ur 80% PSA 175 A˚ 2 O N log P −0.51 O CO2H 529

t1/ 1.2±0.2h V 0.21±0.04 TICARCILLIN HO2C 2 H H F Low CL 1.6±0.3 N S pb 55–65% Mwt 384.4 S O N ur 77±12% PSA 178 A˚ 2 O log P 1.24 CO2H

t1/ 4–6 h (iv) V 0.27–0.30 TEMOCILLIN HO2C 2 H OMe F – CL 0.4–0.7 N S pb 75–88% Mwt 414.5 S O N ur 67–72% PSA 187 A˚ 2 O log P 7.19 CO2H

1/ PhO O t 2 1.2 h V – CARFECILLIN ∗ ∗ H H F 43% CL – acid (carbenicillin) on oral N S pb – Mwt 454.5 dosing of carfecillin ur – PSA 138 A˚ 2 O N O log P 2.85 CO2H

1/ t 2 1.2 h V – CARINDACILLIN O O F 69%∗ CL – ∗acid (carbenicillin) on oral H H N S pb – Mwt 494.6 dosing of carindacillin ur – PSA 138 A˚ 2 O N log P 3.58 O CO2H

Table 70.2 Cephalosporins and related compounds. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

t1/ 0.9±0.2h V 0.26±0.03 CEPHALEXIN NH2 2 H H ± . ± . N S F 90 9% CL 4 3 1 1 pb 14±3% Mwt 347.4 O N ur 91±18% PSA 138 A˚ 2 O log P 0.35 CO2H

t1/ 0.9±0.3h V 0.46±0.07 CEPHRADINE NH2 2 H H ± . ± . N S F 94 12% CL 4 8 0 6 pb 14±3% Mwt 349.4 O N ur 86±10% PSA 138 A˚ 2 O log P 0.48 CO2H

(continued overleaf ) 530 70 β-Lactams

1/ NH t 2 1.0 h V 0.25 CEFROXADINE 2 H H N S F 100% CL 3.1 pb 10% Mwt 365.4 O N ur 71% PSA 147 A˚ 2 OMe O log P 1.46 CO2H

t1/ 0.7±0.3h V 0.36 CEFACLOR NH2 2 H H ± . ± . N S F 52 17% CL 6 1 1 5 pb 25% Mwt 367.8 O N ur 52±17% PSA 138 A˚ 2 Cl O log P 0.14 CO2H

t1/ 1.2±0.3h V 0.32±0.10 LORACARBEF NH2 2 H H ± N F 94 16% CL 1.7 pb 25% Mwt 349.8 O N ur 94±16% PSA 113 A˚ 2 Cl O log P −1.60 CO2H

t1/ 1.2±0.2h V 0.24±0.05 CEFADROXIL NH2 2 H H . ± . N S F 100% CL 2 9 0 7 pb 20% Mwt 363.4 O N ur 93±4% PSA 158 A˚ 2 HO O log P −0.25 CO2H

NH t1/ 1.5±0.4h V 0.22±0.02 CEFPROZIL 2 H H 2 N S F 90±10% CL 3.0±0.4 cis/trans 9 : 1 pb 40±4% Mwt 389.4 O N ur 73±7% PSA 158 A˚ 2 HO O log P −0.60 CO2H

1/ NH HN N t 2 1.2–1.4 h V 0.22 CEFATRIZINE 2 H H N S N F 50–75% CL 3.3 pb 60% Mwt 462.5 O N S ˚ 2 HO O ur 42–60% PSA 225 A − . CO2H log P 1 07

1/ . ± . . ± . OH N N t 2 0 8 0 1h V 0 16 0 05 CEFAMANDOLE H H ± . ± . N S N N F 96 3% CL 2 8 1 0 pb 74% Mwt 462.5 O N S ur 96±3% PSA 201 A˚ 2 O log P −0.04 CO2H 531

t1/ 4.4±0.8h V 0.11±0.01 CEFONICID HO3S 2 OH N N . ± . H H F –CL032 0 06 N S N N pb 98% Mwt 542.6 ur 88±6% PSA 264 A˚ 2 O N S − . O log P 2 29 CO2H

1/ . ± . . ± . HO C t 2 2 6 0 5h V 0 14 0 04 CEFORANIDE 2 N N H H F – CL 0.26–0.66 N S N N pb 80–82% Mwt 519.6 ur 84±3% PSA 244 A˚ 2 O N S − . O log P 0 36 NH2 CO2H

1/ . ± . . ± . H H t 2 0 7 0 2h V 0 21 0 06 CEPHAPIRIN N S O . ± . S F –CL69 2 0 Metabolism: O-deacetylation, pb 62±4% Mwt 423.5 then lactonization O N O 2 O ur 48±7% PSA 177 A˚ CO H log P −0.41 N 2

1/ H H t 2 0.9 h (iv) V 0.41 CEPHACETRILE N S O F Low CL 6.3 ∗ NC rabbit pb 27%∗ Mwt 339.3 O N O ˚ 2 O ur – PSA 162 A log P −1.60 CO2H

1/ . ± . . ± . H H t 2 0 6 0 3h V 0 26 0 11 CEPHALOTHIN S N S O F –CL6.7±1.7 pb 71±3% Mwt 396.4 O N O ˚ 2 O ur 52% PSA 167 A log P 0.09 CO2H

1/ . ± . . ± . H OMe t 2 0 8 0 1h V 0 25 0 10 CEFOXITIN S N S O NH2 F Low CL 3.3 O N O pb 73% Mwt 427.5 O ur 79±5% PSA 202 A˚ 2 CO2H log P 0.00

1/ H H t 2 1.5 h (iv) V 0.46 CEPHALORIDINE S N S F Low CL 3.3 O N N pb 20% Mwt 416.5 O ur – PSA 90.6 A˚ 2 CO2H log P −4.26

(continued overleaf ) 532 70 β-Lactams

1/ HO S NH t 2 1.8 h V 0.28 CEFSULODIN 3 H H 2 N S F –CL1.85 O pb 15% Mwt 533.6 O N N ˚ 2 O ur – PSA 188.1 A − . CO2H log P 5 72

1/ ∗ . ∗ t 2 2–3 h V 0 37 CEFTAROLINE FOSAMIL N F Low CL – ∗dephosphorylated metabolite OEt ∗ N pb <20% Mwt 684.7 (ceftaroline) on iv dosing of OH H HO H 2 P N N S ur – PSA 207.5 A˚ prodrug O N N log P −4.79 S N O N S H O S CO2H

1/ ∗ t 2 1h V 0.13 CEFCANEL DALOXATE O F 40%∗ CL 2.6 ∗acid (cefcanel) on oral dosing H N 2 pb – Mwt 661.7 of ester O N ∗ H H ur <70% PSA 268 A˚ 2 Diester prodrug of cefcanel N S N S log P 2.85 (hydroxyacid) O N S O O O O O O

1/ . ± . . ± . t 2 1 8 0 4h V 0 14 0 04 CEFAZOLIN N > . ± . H H F 90% CL 0 95 0 17 N S N S ± N pb 89 2% Mwt 454.5 N ur 80±16% PSA 235 A˚ 2 N N O N S − . O log P 0 70 CO2H

1/ . ± . t 2 1 6 0 2h V 0.15 CEFAZEDONE N H H F –CL–Similar PK as cefazolin Cl N S N S N pb 93% Mwt 548.4 ˚ 2 O N S ur – PSA 212 A O O log P −0.42 Cl CO2H

1/ . ± . . ± . N N t 2 1 5 0 3h V 0 18 0 04 CEFMETAZOLE H OMe ± . ± . N S N N F 80 20% CL 1 45 0 10 S pb 70% Mwt 471.5 O N S ur 80±13% PSA 239 A˚ 2 CN O log P −0.62 CO2H 533

1/ N N t 2 50 min V 0.2 FLOMOXEF H OMe N O N N F –CL4.1 S pb 29% Mwt 496.5 O N S OH ˚ 2 F F O ur 47% PSA 220 A − . CO2H log P 2 43

1/ N N t 2 2.4 h V –CEFMINOX H OMe N S N N F Low CL – S pb – Mwt 519.6 H2N O N S ˚ 2 O ur – PSA 279 A − . CO2H CO2H log P 0 68

1/ . ± . . ± . CO2H t 2 3 6 1 0h V 0 14 0 03 CEFOTETAN O S N N F –CL0.23Metabolism: isomerization to H OMe N N pb 85±4% Mwt 575.6 1,2-thiazole (isothiazole; NH S N S 2 ur 67±11% PSA 316 A˚ 2 nucleophilic attack of O N S log P 2.34 amide-NH at S) O CO2H

1/ . ± . . ± . HO C N N t 2 2 1 0 7h V 0 25 0 08 MOXALACTAM, 2 H OMe N O N N F 3% CL 1.0 LATAMOXEF pb 53–67% Mwt 520.5 Mixture of diastereomers O N S ± ˚ 2 HO O ur 76 12% PSA 232 A − . CO2H log P 2 56

1/ . ± . . ± . OH t 2 1 7 0 6h V 0 27 0 08 CEFDINIR N . ± . H H F 16–21% CL 0 5 0 2 N N S pb 60–70% Mwt 395.4 2 H2N ur 12–18% PSA 212 A˚ S O N − . O log P 1 78 CO2H

1/ . ± . . ± . OMe t 2 1 8 0 7h V 0 36 0 19 CEFTIZOXIME N H H F Low CL 1.1 N N S pb 28±5% Mwt 383.4 2 H2N ur 93±8% PSA 201 A˚ S O N O log P 0.59 CO2H

1/ . ± . t 2 2.5 h V 0 21 0 03 CEFTIBUTEN CO2H H F 100% CL/F 1.3 N S N pb 62–64% Mwt 410.4 H N H 2 ur 7–26% PSA 216 A˚ 2 S O N O log P −3.19 CO2H

(continued overleaf ) 534 70 β-Lactams

t1/ 3.0±0.4h V 0.30±0.03 CEFIXIME O CO2H 2 N ± . ± . H F 47 15% CL 1 3 0 2 N N S pb 67±1% Mwt 453.5 2 H2N H ur 41±7% PSA 238 A˚ S O N O log P 1.00 CO2H

1/ . ± . . ± . O CO H t 2 1 6 0 1h V 0 23 0 02 CEFTAZIDIME N 2 H F Low CL 1.05 N S N pb 21±6% Mwt 547.6 H2N H ± ˚ 2 S O N N ur 84 4% PSA 188.4 A O log P −4.98 CO2H

t1/ 1.7±0.2h V 0.16±0.02 AZTREONAM O CO2H 2 N F <1% CL 1.3±0.1 No metabolites identiﬁed N N pb 56% Mwt 435.4 H N H ur 68±8% PSA 238 A˚ 2 2 O N S log P −0.66 O SO3H

t1/ 1.6–1.8 h∗ V 0.18 CARUMONAM O CO2H 2 N NH2 F –CL1.5∗iv N N O O pb 28% Mwt 466.4 H N H ur 75–81% PSA 291 A˚ 2 2 O N S log P −2.26 O SO3H

1/ ∗ OMe t 2 1.7–2.2 h V 0.24 CEFPIROME N ∗ H H F –CL1.9 iv N S N pb 10% Mwt 515.6 H N 2 ur 80–90% PSA 151.1 A˚ 2 S O N N O log P −4.08 CO2H

t1/ 2.7–4.2 h∗ V 0.054 CEFODIZIME OMe HO2C 2 N F –CL0.61∗iv H H N N S S N pb 82% Mwt 584.7 ˚ 2 H2N ur 80% PSA 304 A S O N S O log P 2.55 CO2H

1/ . ± . . ± . OMe t 2 1 1 0 3h V 0 23 0 06 CEFOTAXIME N H H F Low CL 3.7±0.6 Active metabolite: desacetyl N S O ± 1/ . N pb 36 3% Mwt 455.5 (t 2 1 5h) H2N ur 55±10% PSA 227 A˚ 2 S O N O O log P 1.20 CO2H 535

1/ . ± . ∗ . ± . OMe t 2 1 7 0 6h V 0 20 0 04 CEFUROXIME AXETIL N ∗ . ∗ ∗ H F 68% CL 0 94 acid (cefuroxime) on oral H ∗ O N S O NH2 pb 33±6% Mwt 510.5 dosing of ester ur 96±10%∗ PSA 214 A˚ 2 Metabolism: ester hydrolysis, O N O O O log P 0.85 O-demethylation O O O

1/ ∗ OMe t 2 2.1–2.9 h V 0.3–0.4 CEFETAMET N ∗ H H F – CL 1.7–2.3 iv N N S pb 22% Mwt 397.4 ∗ 2 H2N ur 63–99% PSA 201 A˚ S O N − . O log P 0 24 CO2H

1/ . ± . ∗ . ∗ OMe t 2 2 5 0 3h V 0 3 CEFETAMET PIVOXIL N ∗ ∗ ∗ H H F 45±13% CL 2.9–6.4 acid (cefetamet) on oral N S N pb – Mwt 511.6 H N dosing of ester 2 ∗ 2 S O N ur 27–55% PSA 216 A˚ Prodrug of cefetamet (acid), O log P 2.44 no prodrug can be detected in O O O O plasma after po dosing

1/ . ± . ∗ . ± . ∗ OMe t 2 1 6 0 4h V 0 14 0 03 CEFDITOREN PIVOXIL N N ∗ ∗ ∗ H H F 14% CL 0.1–0.3 acid (cefditoren) on oral N S S N pb 88%∗ Mwt 620.7 dosing of ester H N 2 2 S O N ur – PSA 257 A˚ O log P 3.35 O O O O

1/ . ± . ∗ . ± . ∗ OMe t 2 2 3 0 3h V 0 46 0 03 CEFPODOXIME PROXETIL N ∗ ∗ ∗ H H F 52±5% CL 2.4±0.1 acid (cef) on oral dosing of N S N pb 27±4%∗ Mwt 557.6 ester H2N ± ∗ ˚ 2 S O N OMe ur 81 5% PSA 235 A O O log P 2.17 O O O O

1/ ∗ OMe t 2 1.9–2.5 h V 0.28 CEFEPIME N ∗ H H F –CL2.2 iv N S N pb 16–22% Mwt 481.6 Metabolism: epimerization, H2N ∗ ˚ 2 S O N N ur 76–85% PSA 147.2 A N-dealkylation (to O log P −4.40 N-methylpyrrolidine) CO2H

(continued overleaf ) 536 70 β-Lactams

1/ t 2 0.6–1.1 h V – CEFOTIAM N F –CL6.7±1.5 Prodrug: cefotiam hexetil; F: N N H H pb 40% Mwt 525.6 46% of cefotiam after oral N N S N N ur 82% PSA 251 A˚ 2 dosing of prodrug H2N log P 0.23 S O N S O CO2H

1/ . ± . . ± . O t 2 7 3 1 6h V 0 16 0 03 CEFTRIAXONE OMe O F Low CL 0.24±0.06 N NH H H pb 90–95% Mwt 554.6 N S N N N ur 49±13% PSA 288 A˚ 2 H2N − . S O N S log P 0 25 O CO2H

1/ ∗ OMe t 2 1.1–1.6 h V 0.23 CEFMENOXIME N N N ∗ H H F –CL3.3 iv N S N N N pb 50–60% Mwt 511.6 H2N ∗ ˚ 2 S O N S ur 81% PSA 270 A O log P −0.91 CO2H

1/ . ± . . ± . N t 2 2 2 0 3h V 0 14 0 03 CEFOPERAZONE . ± . N O F –CL12 0 2 Metabolism: hydrolysis of O pb 89–93% Mwt 645.7 oxalamide (CON–CONH) O NH N N ± 2 H H ur 29 4% PSA 266 A˚ N N N S log P 1.43 O N S HO O CO2H

1/ . ± . ∗ . ± . N t 2 5 4 1 4h V 0 15 0 03 CEFPIRAMIDE F –CL0.43±0.08 ∗iv O pb 95–99% Mwt 612.6 ∗ OH NH N N ur 17–22% PSA 263 A˚ 2 H H N S N N log P 0.17

O N S HO O CO2H 537

1/ . ± . O O t 2 1.9 h (iv) V 0 30 0 05 CEFPIMIZOLE S F –CL1.7±0.3 O HO H H pb – Mwt 671.7 N S N N ur 80% PSA 240.0 A˚ 2 H O N N log P −5.68 N CO H H 2 O CO2H

∗ OH t1/ 3.3 h V 0.27 CEFTOBIPROLE N 2 H H F –CL1.5MEDOCARIL N S N pb 16–38% Mwt 690.7 ∗amine (ceftobiprole) on iv S N O N ur 70% PSA 310 A˚ 2 dosing of carbamate O H N log P −1.02 2 CO2H O N

O O N O O O

71 Prostaglandin Analogs

Arachidonic acid is the biochemical precursor of the prostaglandins, prostacyclins, thromboxanes, and leukotrienes (Scheme 71.1). These hormones are carboxylic acids with 20 carbon atoms, also called eicosanoids. In 1930, the American gynecologists Raphael Kurzrok and Charles Lieb discovered that semen contained these substances, which cause the contraction or relaxation of uterine muscle. Since then, eicosanoids were found to be involved in a broad spectrum of biological activities.

CO2H Cyclooxygenase-1 O CO2H (COX-1) O

Arachidonic acid O PGG2 OH

Thromboxane O CO H synthase CO H 2 O 2 O O

PGH2 OH TXA2 OH

Isomerase Hydrolysis HO OH CO H 2 CO2H HO O HO OH OH

PGE2, a prostaglandin TXB2, a thromboxane

Scheme 71.1 Biosynthesis of eicosanoids. Like the steroid hormones, eicosanoids are extremely potent. Oral doses of misoprostol, an analog of prostaglandin E2 (PGE2) suitable for the treatment of gastric ulcers, range from only 0.4 to 0.8 mg daily. Because natural prostaglandins have low oral bioavailabilities and short half-lives, synthetic analogs with improved pharmacokinetics (PK) have been prepared (Table 71.1). These are used as abortifacients, gastroprotectants, and antithrombotics (e.g., for treatment of acute myocardial infarction).

Typical metabolic transformations include oxidation of hydroxyl groups, reduction of ketones, hydroxylation, and oxidative degradation. As for most nonhalogenated alkanes, these transformations proceed quickly, and most prostaglandin analogs undergo extensive ﬁrst-pass metabolism.

Table 71.1 Prostaglandin analogs. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ O t 2 5–10 min V 0.8 ALPROSTADIL, PGE1 CO2H F 14% CL 20 Treatment of erectile pb 93% Mwt 354.5 dysfunction ur 0% PSA 94.8 A˚ 2 Metabolism: oxidation of allylic HO OH log P 2.75 OH to ketone

1/ ∗ O t 2 1–2 h V – LUBIPROSTONE ∗ CO2H F Low CL – reduced diﬂuoroketone pb 94% Mwt 390.5 Laxative ur 0% PSA 83.8 A˚ 2 Metabolism: reduction of O log P 2.85 diﬂuoroketone to alcohol HO F F

1/ t 2 1–5 min V – DINOPROSTONE CO2H F –CL–Abortifacient O pb 73% Mwt 352.5 Metabolism: hydrogenation of ur Low PSA 94.8 A˚ 2 double bonds, oxidation of log P 2.97 exocyclic alcohol to ketone, oxidation of methyl to CO2H, HO OH oxidative degradation of carboxyalkyl group

1/ . ± . CO2H t 2 2 0 0 5h V 0.08 CICAPROST F 100% CL 3.8 Inhibitor of platelet O pb – Mwt 374.5 aggregation, vasodilator ur 60% PSA 87 A˚ 2 H H log P 1.94

OH OH

(continued overleaf ) 540 71 Prostaglandin Analogs

t1/ 0.3–0.5 h V 0.6–0.8 ILOPROST CO2H 2 F 15–20% CL 16–20 Inhibitor of platelet pb 60% Mwt 360.5 aggregation, vasodilator; ur 0% PSA 77.8 A˚ 2 mixture of diastereomers log P 3.28 Metabolism: oxidation and H H hydroxylation of alkyl chains, oxidation of allylic OH to ketone OH OH

1/ t 2 1h V –BERAPROST HO2C F –CL–Antithrombotic, vasodilator pb – Mwt 398.5 Metabolism: oxidative O ur 0% PSA 87.0 A˚ 2 degradation of arylbutyric acid H H log P 2.87 to arylacetic acid, propargylic hydroxylation, isomerization of OH OH allylic alcohol to saturated ketone

1/ t 2 0.9 h (iv) V 0.8–1.1 TREPROSTINIL O F –CL11Antihypertensive HO C 2 pb 91% Mwt 390.5 Metabolism: glucuronidation, ˚ 2 H H ur 4% (iv) PSA 87.0 A oxidation of octyl chain log P 3.50

OH OH

1/ O t 2 45 min (iv) V 0.67 BIMATOPROST F –CL25Lowers intraocular pressure, N pb 88% Mwt 415.6 antiglaucoma agent HO H ur – PSA 89.8 A˚ 2 Metabolism: N-deethylation, log P 1.98 glucuronidation, hydrolysis of amide HO OH

1/ ∗ . ∗ t 2 17–86 min V 2 6 (rat) TRAVOPROST ∗ O F Negligible CL – acid on oral dosing of ester pb – Mwt 500.6 Lowers intraocular pressure, O HO ur <2%∗ PSA 96.2 A˚ 2 antiglaucoma agent log P 3.98 Metabolism of acid: hydrogenation of double bond, O CF 3 oxidation to 15-ketone, oxidative HO OH degradation of upper side chain 71 Prostaglandin Analogs 541

1/ ∗ O t 2 17 min V 0.16 LATANOPROST F –CL–∗acid ∗ HO O pb 87% Mwt 432.6 Lowers intraocular pressure, ur – PSA 87.0 A˚ 2 antiglaucoma agent log P 3.65

HO OH

1/ ∗ O t 2 14 min V – UNOPROSTONE ISOPROPYL F –CL–∗acid HO O pb – Mwt 424.6 Lowers intraocular pressure, ur – PSA 83.8 A˚ 2 antiglaucoma agent log P 4.63

HO O

1/ t 2 2h V 17 SULPROSTONE O O O F –CL–Abortifacient S Metabolism: elimination of O N pb 20–30% Mwt 465.6 H ur Traces PSA 138 A˚ 2 water (to yield cyclopentenone), log P 1.52 hydrogenation of trans-oleﬁn and cyclodehydration (to yield O pyran), hydrolysis of HO OH acylsulfonamide to CO2H

1/ . ± . ∗ ± ∗ t 2 0 5 0 4h V 14 8 MISOPROSTOL O ∗ F >80%∗ CL 240±100∗ acid on oral dosing of ester pb 81–89%∗ Mwt 382.5 Antiulcerative; prodrug, not O O ur 1–4%∗ PSA 83.8 A˚ 2 detectable in plasma after oral OH log P 3.80 dose; mixture of two diastereomers HO Metabolism: oxidative degradation of alkyl chains

1/ CO2H t 2 4–49 min V 0.16 NOCLOPROST Cl F 2% CL 13.2 Gastroprotective pb – Mwt 401.0 ur – PSA 77.8 A˚ 2 log P 4.28 HO OH

(continued overleaf ) 542 71 Prostaglandin Analogs

1/ ∗ t 2 1.1–1.4 h V 0.8–0.9 VAPIPROST F – CL 7.3–10.3 ∗iv N pb – Mwt 477.6 Thromboxane antagonist CO2H ur <1% PSA 70.0 A˚ 2 HO log P 5.68 O

72 Sartans

One of the strategies to treat hypertension (‘‘the silent killer’’) is the administration of an angiotensin II antagonist (Chapter 53). Since the 1970s, a number of peptidomimetics were prepared for this purpose, but all the antagonists found (e.g., saralasin) were also partial agonists and useless because of their lack of oral bioavailability. The first breakthrough in the development of a small-molecule angiotensin II antagonist was achieved in 1982 by Furakawa at Takeda, Japan [1]. His group patented a series of imidazole acetic acids, including the compounds S-8307 and S-8308 (Scheme 72.1), which were weak but selective angiotensin II antagonists devoid of agonistic activity. These imidazole derivatives were used as leads by David J. Carini and John V. Duncia at DuPont, who in 1983 started to optimize their potency and pharmacokinetic (PK) properties to finally arrive at losartan in March 1986. The main reason for DuPont’s endeavor and final success was that the newly hired, unexperienced pharmacologist Pancras C. Wong tested S-8307 in rats at an unusually high concentration (100 mg kg−1). This experiment clearly proved that S-8307 was indeed a selective, competitive angiotensin II antagonist, which worked in vivo. Similar experiments at lower concentrations, which had probably been conducted at Takeda and other companies, would not have revealed any antihypertensive activity of S-8307.

Cl Cl Cl N N N CO2H CO2H CO2H N N N

Cl O2N CO2H S-8307 S-8308 EXP6155 µ µ IC50 40 M 15 M 1.2 µM

Cl Cl Cl N N N CO2Me OH OH N N N N N N NH O CO2H CO2H N H Losartan EXP6803 EXP7711 µ 0.019 µM IC50 0.12 µM 0.23 M t 1/2 2 h, F 33–36%

Scheme 72.1 Development of losartan.

Because the pharma team at DuPont was small and unexperienced, they opted for a collaboration with Merck & Co. to push forward the clinical development and marketing of the new drug. Losartan was approved by the FDA in 1995 and generated sales of more than $3 billion by 2005. Since then, a number of other angiotensin II antagonists have been developed as antihypertensive drugs (Table 72.1). These usually show fewer side effects than the angiotensin-converting enzyme (ACE) inhibitors. Most sartans have low oral bioavailability, mainly because of poor absorption from the GI tract. These molecules are too large and too hydrophilic (large polar surface area (PSA)) to be efﬁciently absorbed. To enhance their lipophilicity, esters have been occasionally used as prodrugs.

Reference

1. (a) Bhardwaj, G. (2006) How the anti-hypertensive losartan was discovered. Expert Opin. Drug Discov., 1, 609–618; (b) Timmermans, P.B., Wong, P.C., Chiu, A.T., Herblin, W.F., Benﬁeld, P., Carini, D.J., Lee, R.J., Wexler, R.R., Saye, J.A.M., and Smith, R.D. (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol. Rev., 45, 205–251. 545

Table 72.1 Antihypertensive angiotensin II receptor antagonists (sartans). V in l kg−1;CLin ml min−1 kg−1; Mwt in g mol−1.

1/ . ± . t 2 6 8 2 3h V 0.2 EPROSARTAN ± ∗ ∗ S F 13 7% CL 1.7–2.0 owing to poor absorbtion from N pb 98% Mwt 424.5 GI tract ˚ 2 N CO2H ur 2–3% PSA 116 A Metabolism: acyl glucuronidation log P 4.96

CO2H

1/ t 2 11–15 h V 0.8–1.3 IRBESARTAN N F 60–80% CL 2.4–2.7 Metabolism: hydroxylation at pb 90–96% Mwt 428.5 butyl and cyclopentane, O N N N ur 1–2% PSA 87.1 A˚ 2 glucuronidation at tetrazole N NH log P 4.50

1/ . ± . Cl t 2 2 0 0 5h V 0.4–0.5 LOSARTAN N F 33–36% CL 6.8–8.5 Metabolism: oxidation of alcohol OH N N N pb 98.7% Mwt 422.9 to carboxylic acid, hydroxylation ˚ 2 N NH ur 9–12% PSA 92.5 A of butyl, glucuronidation of log P 3.46 tetrazole

1/ ± Cl t 2 7 3h V 0.13–0.17 EXP 3174 N F –CL0.6Main active metabolite of losartan pb 99.8% Mwt 436.9 N CO2H N N ˚ 2 N NH ur 55% PSA 105 A log P 4.79

1/ ∗ ∗ OH t 2 10–15 h V 0.21–0.28 OLMESARTAN MEDOXOMIL F 26%∗ CL – Prodrug of olmesartan (carboxylic N ∗ O pb 99% Mwt 558.6 acid) ∗ 2 ∗ N N N ur 35–50% PSA 154 A˚ acid after oral administration of O O N NH log P 5.23 ester O O

(continued overleaf ) 546 72 Sartans

t1/ 10±3h∗ V 0.13∗ CANDESARTAN CILEXETIL N 2 F 15–40%∗ CL 0.4–3.2∗ ∗acid (candesartan) on oral O N N > ∗ O N pb 99% Mwt 610.7 dosing of ester O N NH ur 33–50%∗ PSA 143 A˚ 2 Further metabolism: O O O log P 7.79 O-deethylation

t1/ 9–13 h V 0.13 CANDESARTAN N 2 F 15–40% CL 0.4–3.2 N O N N pb >99% Mwt 440.5 HO C 2 N NH ur 33–50% PSA 114 A˚ 2 log P 5.01

1/ ∗ t 2 11 h V 0.25 AZILSARTAN N ∗ ∗ O F 60% CL – drug on oral dosing of prodrug N O O pb >99% Mwt 456.5 azilsartan medoxomil HO C 2 N NH ur 15%∗ PSA 115 A˚ 2 Metabolism: O-deethylation, log P 5.63 decarboxylation

1/ t 2 24 h V 6.6–7.3 TELMISARTAN N N F 42–57% CL 12.3 Metabolism: glucuronidation pb 99.5% Mwt 514.6 N N N N ur <1% PSA 72.9 A˚ 2 N NH log P 7.73

1/ . ± . t 2 5 3 0 6h V – TASOSARTAN N F 60–79% CL – Metabolism: 4-hydroxylation of pb 99.8% Mwt 411.5 piperidin-2-one, then elimination N N O N N 2 ur – PSA 101 A˚ of water, hydroxylation of 7-CH3, N NH log P 3.42 conversion to enoltasosartan (see below) 547

1/ ± OH t 2 41 2h V – ENOLTASOSARTAN F –CL–Main active metabolite of N pb – Mwt 425.4 tasosartan N N O N N ur – PSA 121 A˚ 2 N NH log P 2.96

1/ . ± . O t 2 7 3 2 2h V 0.24 VALSARTAN F 23–39% CL 0.51 Metabolism: hydroxylation at N CO H N N 2 pb 85–99% Mwt 435.5 CH CH N NH 2 3 ur 7–30% PSA 112 A˚ 2 log P 4.74

73 Statins

Numerous studies in animals and humans have proven that high plasma levels of cholesterol (hypercholesterolemia) strongly enhance the mortality from coronary artery disease. It has also been shown that drug therapy for hypercholesterolemia is highly effective in reducing risk for cardiac, vascular, and cerebrovascular events. Hypercholesterolemia may be controlled by diet or by treatment with niacin, ﬁbrates, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. HMG-CoA reductase catalyzes the rate-determining step of the biosynthesis of cholesterol (Scheme 73.1).

O OH O HMG-CoA O OH OH OH reductase P P O S CoA O OH O O OH O O 3-Hydroxy-3-methylglutaryl Mevalonate Dimethylallyl pyrophosphate coenzyme A

H H

H H HO Squalene Cholesterol

Scheme 73.1 Biosynthesis of cholesterol.

The ﬁrst natural HMG-CoA reductase inhibitor (mevastatin or compactin) was isolated from a Penicillium mold in 1976. Two years later, a second inhibitor, closely related to mevastatin (lovastatin or mevinolin), was isolated from cultures of Aspergillus. Fortunately, it was soon discovered that the lipophilic, synthetically demanding decalin substructure of mevastatin and lovastatin allowed ample structural modiﬁcations without loss of inhibitory activity. This led to the development of numerous HMG-CoA reductase inhibitors devoid of decalin substructure, which have become bestselling drugs (Table 73.1). If compared to the natural products, the newer HMG-CoA reductase inhibitors are metabolically more stable and show higher oral bioavailabilities and longer half-lives. Their synthesis is also much easier.

Table 73.1 Statins (HMG-CoA reductase inhibitors). V inlkg−1;CLinmlmin−1 kg−1; Mwt in gmol−1.

1/ . ± . t 2 1 4 0 3h V 0.87 LOVASTATIN O F <5% CL 11±7 Antilipemic, CYP3A4 substrate O pb 95% Mwt 404.5 Metabolism: 3 -and ′ OH OH 2 6 H ur Negligible PSA 72.8 A˚ 6 -hydroxylations, 3 -methyl log P 4.31 hydroxylation, oxidation of alcohol 3′ CO2H to ketone, glucuronides

t1/ 1.9 h V 2.3 (dog) SIMVASTATIN O 2 F <5% CL 7.6 Antilipemic, CYP3A4 substrate O pb 94% Mwt 418.6 OH OH H ur <5% PSA 72.8 A˚ 2 log P 4.72

CO2H

1/ . ± . . ± . t 2 1 8 0 8h V 0 46 0 04 PRAVASTATIN O F 18±8% CL 3.5±2.4 Antilipemic pb 43–48% Mwt 424.5 Metabolism: reversible lactone HO O OH OH ± ˚ 2 hydrolysis, hydroxylation at H ur 47 7% PSA 124 A log P 2.21 MeCH2, 1,4-dihydroxylation of CO H diene, epimerization, and hydroxy 2 group 1,5-migration of pentadienol

1/ ± F t 2 15 7h V 5.9 ATORVASTATIN F 14% CL 31 Antilipemic pb >98% Mwt 558.6 Metabolism: 2- and OH OH ur <2% PSA 107 A˚ 2 4-hydroxylations of aminophenyl N log P 4.13

CO2H PhHN O

1/ . ± . F t 2 2 7 1 3h V 0.15–0.42 FLUVASTATIN F 9–50% CL 7.9–16.2 Substrate and inhibitor of CYP2C9 pb >99% Mwt 411.5 Metabolism: 5- and OH OH ur <1% PSA 82.7 A˚ 2 6-hydroxylations of indole, log P 4.57 N-deisopropylation

N CO2H

(continued overleaf ) 550 73 Statins

1/ F t 2 11 h V 2.3 PITAVASTATIN F 51–60% CL – Antilipemic pb >99% Mwt 421.5 Metabolism: reversible OH OH ur <5% PSA 90.7 A˚ 2 lactonization log P 3.45 CO H N 2

1/ F t 2 2–4 h V 0.33 CERIVASTATIN F 39–100% CL 2.9–3.1 Metabolism: O-demethylation, pb >99% Mwt 459.6 hydroxylation of CCH3; withdrawn MeO OH OH ur 0% PSA 99.9 A˚ 2 in 2001 because of toxicity in log P 3.71 combination with gemﬁbrozil

CO H N 2

1/ F t 2 18–25 h V 1.7 ROSUVASTATIN F 20% CL 10.5 Antilipemic pb 88% Mwt 481.5 Metabolism: N-demethylation OH OH ur 10% PSA 149 A˚ 2 log P 0.42 O O N S CO H N N 2

74 Folic Acid Analogs (Antifolates)

Folic acid (vitamin B9) is involved in the biosynthesis of nucleosides. A dietary deﬁciency of folic acid causes anemia and a decline in the number of blood- generating bone marrow cells. While investigating the effect of folic acid analogs on the growth of cancer cells, Sidney Farber found that some analogs promoted cell growth while others effectively suppressed it. During 1947, aminopterin and methotrexate were shown to induce temporary remissions in 30% of children with leukemia. In 1963, Roy Hertz discovered that antifolates consistently cured choriocarcinoma, the ﬁrst instance of a cure for a solid tumor. Methotrexate can also be used to treat psoriasis and as an immunosuppressant. Antifolates (Table 74.1) are inhibitors of dihydrofolate reductase, and thereby block the biosynthesis of thymine and purine. The main metabolic pathways include conjugation with glutamic acid and heteroaromatic hydroxylation.

Table 74.1 Folic acid analogs. V inlkg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ . ± . t 2 3 6 0 3h V 0.6 AMINOPTERIN HO2C N N NH2 ± H F 84 8% CL – Antineoplastic HO C N N 2 N pb – Mwt 440.4 ur – PSA 219 A˚ 2 HN NH2 log P −0.93 O

t1/ 7.2±2.1h V 0.55±0.19 METHOTREXATE HO C N N NH 2 2 2 F 70±27% CL 2.1±0.8 Antineoplastic, antirheumatic HO C N N ± 2 N pb 46 11% Mwt 454.4 Metabolite: 7-hydroxy ur 81±9% PSA 211 A˚ 2 HN NH2 log P −0.45 O

(continued overleaf )

t1/ 5.3±1.2h V 0.2 PT-523 O CO H 2 2 F –CL0.5Antineoplastic HN pb – Mwt 573.6 2 N N NH2 ur 40±15% PSA 248 A˚ H − . HO C N N log P 0 46 2 N

HN NH2 O

1/ HO2C N N NH2 t 2 7–12 h V – EDATREXATE F –CL6.4±3.6 Antineoplastic HO C N 2 N pb 30% (rat) Mwt 467.5 Metabolite: 7-hydroxy 2 HN NH2 ur 13–55% PSA 207 A˚ O log P 1.54

1/ ∗ HO2C N N NH2 t 2 12–18 h V 0.6–1.6 PRALATREXATE F – CL 2.9–6.4 ∗iv HO C N 2 N pb 67% Mwt 477.5 Antineoplastic ∗ ˚ 2 HN NH2 ur 31–38% PSA 207 A Metabolism: glutamylation log P 0.23 O

1/ ± H t 2 43 28 h V – LOMETREXOL HO C N N NH 2 2 F –CL0.8±0.2 Antineoplastic

HO2C NH pb 78% Mwt 443.5 Metabolism: conjugation with ur – PSA 183 A˚ 2 glutamic acid to higher HN O log P 1.23 glutamates O

O 1/ . ± . . ± . t 2 9 3 2 8h V 3 2 1 2 LEUCOVORIN, FOLINIC HO2C N N NH2 F 40–100% CL 3.9±0.8 ACID H HO C N NH pb 40±5% Mwt 473.4 Prodrug of tetrahydrofolic acid; 2 N H ur 10% PSA 216 A˚ 2 mixture of stereoisomers HN O log P −1.43 O

1/ N NH t 2 2–6 d V 0.3–1.0 ZD 9331 N F 80% (dog) CL 0.05–0.31 Antineoplastic N N pb 98% Mwt 532.5 HO2C N NH ur – PSA 166 A˚ 2 HN O log P 1.48

O F 74 Folic Acid Analogs (Antifolates) 553

1/ HO2C t 2 150–380 h V 8 RALTITREXED, TOMUDEX ∗ ∗ HO2C N F 10–20% CL 0.6–1.2 rat pb 95% Mwt 458.5 Antineoplastic HN S N NH ur 20–50% PSA 177 A˚ 2 Metabolism: polyglutamation O log P 0.86 O

1/ ∗ H t 2 3.5 h V 0.3 PEMETREXED HO2C N ∗∗ ∗ F 13% CL 1.4 iv N ∗∗ HO2C pb 81% Mwt 427.4 mice NH 2 ∗ ˚ 2 HN N ur 70–90% PSA 187 A Antineoplastic O H log P −0.70 O

75 Taxanes

In the early 1960s, large collections of natural products were screened at the National Cancer Institute (NCI, US). In 1962, one extract showed remarkable activity against several types of tumor. The active principle, paclitaxel (Taxol), was isolated from the bark of the Western yew tree (Taxus brevifolia) and its structure determined in 1971 by single-crystal X-ray crystallography by Mansukh C. Wani and coworkers. Paclitaxel was approved for treatment of ovarian cancer in 1992. In contrast to the vinca alkaloids, which inhibit microtubule formation, paclitaxel acts by promoting microtubule formation, thereby preventing mitosis. Because of its poor solubility, it has to be solubilized with a detergent, Cremophor EL. Still, this formulation is far from optimal, and further, more soluble taxanes or prodrugs thereof are being developed (Table 75.1) [1].

Reference

1. Skwarczynski, M., Hayashi, Y., and Kiso, Y. (2006) Paclitaxel prodrugs: toward smarter delivery of anticancer agents. J. Med. Chem., 49, 7253–7269.

Table 75.1 Taxanes. V in l kg−1;CLinmlmin−1 kg−1; Mwt in g mol−1.

1/ O t 2 11–18 h V 1.7–3.7 DOCETAXEL HO F – CL 7.0–9.1 Antineoplastic; Metabolism: O O NH O OH pb 93–94% Mwt 807.9 hydroxylation of tert-butyl ur <4% PSA 224 A˚ 2 O and phenyl log P 2.46 OH HO H O O PhCO AcO

1/ O t 2 62 h V 71 CABAZITAXEL MeO F –CL12 Antineoplastic; Metabolism: O O NH O OMe pb 89–92% Mwt 835.9 O-demethylation ur 2.3% (iv) PSA 202 A˚ 2 O log P 3.30 OH HO H O O PhCO AcO

1/ O t 2 20–24 h V 25 RPR-109881A AcO F –CL19 Antineoplastic O O NH O pb – Mwt 831.9 ur 1% PSA 210 A˚ 2 O log P 5.66 OH HO H O O PhCO AcO

1/ ± . ± . O t 2 3 1h V 2 0 1 2 PACLITAXEL, TAXOL AcO F Negligible CL 5.5±3.5 Antineoplastic; Metabolism: O Ph NH O OH pb 95–98% Mwt 853.9 hydroxylation of phenyl ur 5±2% PSA 221 A˚ 2 group and methylene group O log P 3.95 of cyclohexane OH HO H O O PhCO AcO

1/ ± ± O MeS t 2 34 6h V 10 2 BMS-184476 AcO F –CL5.1±0.7 Antineoplastic; Metabolism: O Ph NH O O pb – Mwt 914.0 oxidation to sulfoxide ur – PSA 236 A˚ 2 O log P 5.00 OH HO H O O PhCO AcO

1/ t 2 22 h V – BMS-275183 O ∗ AcO F 24% CL – animals O O NH O OH pb – Mwt 845.9 Antineoplastic; Metabolism: ur <3.5%∗ PSA 240 A˚ 2 ester hydrolysis, O log P 3.49 hydroxylation of tert-butyl OH HO H O O PhCO O CO2Me

(continued overleaf ) 556 75 Taxanes

1/ O t 2 70 h V – ORTATAXEL, BAY 59-8862 AcO F 19–31% CL – Antineoplastic O O NH O OH pb – Mwt 871.9 ur – PSA 246 A˚ 2 O log P 7.56 OH OOH O O O O Bz Ac

1/ ± / ± t 2 167 77 h V F 72 47 DJ-927 ∗ N F 63% CL 6±3 ∗monkey O O pb 92–98% Mwt 882.0 Antineoplastic O ˚ 2 O NH O ur – PSA 202 A N log P 5.73 O OH F HO H O O PhCO AcO

76 Macrocyclic Compounds

A number of bioactive, macrocyclic natural products are being used as drugs or as lead structures. Despite being highly flexible, and thus having an entropic disadvantage when compared to smaller, less flexible molecules, some of these compounds bind to proteins with high affinity and selectivity [1]. Because of the entropic disadvantage of large, flexible compounds, it is unlikely that selective ligands will be found by screening large, oligomeric molecules, prepared randomly. For this reason, most of the compounds listed below originated from natural products. Cyclic peptides are listed in Table 55.1. Rapamycin and tacrolimus were isolated in 1965 and 1975, respectively, from soil bacteria of Easter Island. These compounds bind selectively to a protein involved in the immune response (FK-binding protein 12) and are potent immunosuppressants, used to prevent transplant rejection. The antibiotic erythromycin was also isolated from soil bacteria (1952, J. M. McGuire). Macrolide antibiotics such as erythromycin are bacteriostatic. These lactones bind reversibly to the bacterial 50S ribosomal subunit and thereby inhibit protein biosynthesis. A number of analogs with improved pharmacokinetic (PK) properties have been developed (Table 76.1). Macrolides are important leads for new antibiotics, as antibiotic-resistant bacterial strains continue to emerge (see Ref. [1] in Chapter 70).

Reference

1. Marsault, E. and Peterson, M.L. (2011) Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J. Med. Chem., 54, 1961–2004.

Table 76.1 Macrocyclic compounds. V inlkg−1,CLinmlmin−1 kg−1, Mwt in g mol−1.

1/ t 2 18 h (iv) V 2.7 TEMSIROLIMUS ∗ O OH F 22%∗ CL 7.7 monkey H O O OH Antineoplastic N O pb 86% Mwt 1030.3 2 O O O ur – PSA 242 A˚ Metabolism: exocyclic O HO log P 3.00 ester hydrolysis to O sirolimus OH

O MeO MeO

1/ ± OH t 2 40–86 h V 23 10 RAPAMYCIN, . ± . SIROLIMUS H F 15% CL 4 6 2 0 O pb 92–98% Mwt 914.2 Immunosuppressant N O ur <2% PSA 195 A˚ 2 Metabolism: O O O O log P 4.26 O-demethylation, HO tetrahydropyran O 4-hydroxylation OH

O MeO MeO

1/ N t 2 35 h (iv) V 1.3 ZOTAROLIMUS N F –CL0.7Immunosuppressant N N pb 99% Mwt 966.2 H O ur 0.1% PSA 219 A˚ 2 N O log P 3.59 O O O O HO O OH

O MeO MeO 559

1/ ± . ± . OH t 2 15 7h V 0 88 0 31 TACROLIMUS, FK506 F 16±7% CL 0.70±0.27 Immunosuppressant O N O pb 75–99% Mwt 804.0 CYP3A4 substrate ur <1% PSA 178 A˚ 2 Metabolism: O O OH O log P 4.79 O-demethylation HO O O H OMe

MeO

1/ / Cl t 2 35–92 h V F 40–138 PIMECROLIMUS F –CL/F 13–21 Immunomodulator for O pb 74–87% Mwt 810.5 topical application N O ur 0% PSA 158 A˚ 2 Metabolism: O O OH O log P 5.76 O-demethylation HO O O H OMe

MeO

1/ O t 2 30–43 h V 4.7 EVEROLIMUS ∗ ∗ H F 16% CL 1.5–2.7 rat O N O OH pb 74% Mwt 958.2 Antineoplastic O O O ur Negligible PSA 205 A˚ 2 Metabolism: O HO log P 3.39 hydroxylation O OH

O MeO MeO

1/ . ± . . ± . O t 2 3 3 0 5h V 2 6 0 5 CLARITHROMYCIN F 55±8% CL 7.3±1.9 Antibacterial pb 46±4% Mwt 748.0 HO OMe ur 36±7% PSA 183 A˚ 2 OH OH log P 3.16 O O N

O O O

O OMe

(continued overleaf ) 560 76 Macrocyclic Compounds

1/ . ± . . ± . O t 2 1 6 0 7h V 0 78 0 44 ERYTHROMYCIN F 35±25% CL 9.1±4.1 Antibacterial pb 84±3% Mwt 733.9 CYP3A substrate HO OH ur 12±7% PSA 194 A˚ 2 OH OH log P 1.91 O O N

O O O

O OMe

1/ / O t 2 8–10 h V F 5.5 FLURITHROMYCIN F F Good CL/F 8 Antibacterial pb – Mwt 751.9 HO OH ur – PSA 194 A˚ 2 OH OH log P 1.89 O O N

O O O

O OMe

1/ O O t 2 12 h V 0.44 ROXITHROMYCIN N OMe F 60% CL – Metabolism: pb 96% Mwt 837.1 deglycosylation, N- and HO OH ur <10% PSA 217 A˚ 2 O-demethylation, OH log P 2.84 formaldehyde acetal OH hydrolysis O O N

O O O

O OMe

OH 561

t1/ 16–55 h∗ V 8–16∗ DIRITHROMYCIN O NH 2 F 10%∗ CL – Prodrug of OMe pb 15–30%∗ Mwt 835.1 erythromyclylamine HO O OH ur 2% PSA 196 A˚ 2 (hydrolysis of OH log P 3.38 hemiaminal) ∗erythromyclylamine on O O N oral administration of O O O dirithromycin

O OMe

t1/ 40 h V 31 AZITHROMYCIN N 2 F 37% CL 9 Antibacterial HO OH pb 7–50% Mwt 749.0 Metabolism: N- and OH ur 12% PSA 180 A˚ 2 O-demethylation, OH log P 3.33 hydroxylation, hydrolysis O O N of glycosidic bonds O O O

O OMe

1/ N t 2 10–14 h V 2.0–3.2 TELITHROMYCIN N N F 57% CL – Antibacterial Metabolism: O pb 60–70% Mwt 812.0 ur 20–23% (iv) PSA 172 A˚ 2 N-dealkylation of log P 5.22 imidazole to primary N O OMe alcohol O OH O O N

O O O

OH 1/ ± . ± . OH t 2 18 7h V 0 76 0 52 AMPHOTERICIN B O OH F –CL0.46±0.20 H Antifungal HO O OH OH OH OH O pb >90% Mwt 924.1 CO2H ur 2–5% PSA 327 A˚ 2 O O log P 0.06

HO OH

NH2

(continued overleaf ) 562 76 Macrocyclic Compounds

1/ t 2 27 h V 0.5 IVERMECTIN MeO O O F –CL0.3Antiparasitic (nematodes, O O H O pb 93% Mwt 875.1 arthropods) O O ur 0% PSA 170 A˚ 2 Metabolism: O HO log P 5.97 hydroxylation, MeO O-demethylation OH O H OH

1/ NMe t 2 4–8 h V 6SPIRAMYCIN 2 OH HO F 30–40% CL 8–22 Antibacterial O O pb 18% Mwt 843.1 Metabolism: ˚ 2 O O ur 14% PSA 195.4 A deglycosylation of log P 2.30 disaccharide O O O O O NMe2 OH O OH

1/ OH t 2 1–3 h V – FIDAXOMICIN HO O F Low CL – Antibacterial, RNA pb – Mwt 1058.0 polymerase inhibitor O 2 O O ur 0% PSA 267 A˚ log P 11.0

HO O H O OH

O O O OH Cl MeO O OH OH Cl

1/ ± / ± t 2 47 12 h V F 40 15 RIFABUTIN HO F 20±7% CL/F 12±3 Antibacterial ± AcO OH O pb 85 2% Mwt 847.0 Metabolism: ur 7±3% PSA 206 A˚ 2 O-deacetylation MeO OH O log P 4.49 NH

O NH O N O N 563

1/ . ± . . ± . t 2 3 5 0 8h V 0 97 0 36 RIFAMPIN HO F 90–100% CL 3.5±1.6 Antibacterial pb 89±1% Mwt 822.9 Metabolism: AcO OH O ur 7±3% PSA 220 A˚ 2 O-deacetylation MeO OH OH log P 2.05 NH

O O OH N O N N

1/ t 2 6h V – RIFAXIMIN HO F <0.4% CL – Antibacterial pb 68% Mwt 785.9 Metabolism: deacetylation AcO OH O ur <0.1% PSA 198 A˚ 2 MeO OH OH log P 3.35 NH

O N O N O

1/ O t 2 0.7 h (iv) V 0.39 DALFOPRISTIN O O O S F –CL16Antibacterial pb 18% Mwt 690.9 N HN O ur 0% PSA 185 A˚ 2 O N log P −0.94

N O HO O

1/ N t 2 1–3 h (iv) V 0.7 QUINUPRISTIN F –CL16Antibacterial pb 66% Mwt 1022.2 N ur – PSA 231.2 A˚ 2 N log P 1.97 S N O N O O O O NH O O NH N N H O O HO

(continued overleaf ) 564 76 Macrocyclic Compounds

1/ . ± . . ± . HO t 2 5 2 1 9h V 0 4 0 1 CAPREOMYCIN 1A NH O O 2 H F Low CL 0.61 Antibacterial N NH N N 2 pb – Mwt 668.7 H H ur 57±19% PSA 378.4 A˚ 2 O O NH HN log P −8.65 H H N H N N N 2 2 O H H O O HN

H2N N

1/ ∗ H t 2 4–19 min V 0.7–4.2 RHIZOXIN O O F – CL 35–434 ∗iv pb – Mwt 625.8 Antineoplastic O H ur – PSA 133 A˚ 2 HO O log P 4.30 O N O H O

OMe

1/ O t 2 17–52 h (iv) V 11 IXABEPILONE S F –CL10Analog of epothilone B pb 67–77% Mwt 506.7 (replacement of lactone OH N ur 6% (iv) PSA 140 A˚ 2 by lactam), HN log P 1.77 microtubule-stabilizing agent, antineoplastic O OH O

1/ ∗ O t 2 53–83 h V 36–58 SAGOPILONE S F – CL 10–19 ∗β; α:3min pb – Mwt 543.7 Microtubule-stabilizing OH N ur – PSA 134 A˚ 2 agent, antineoplastic O log P 3.19

O OH O

1/ ∗ t 2 45–65 h V 0.5 TEMOPORFIN ∗ HO OH F –CL0.07iv pb 85–88% Mwt 680.8 Photosensitizer, no N ur Negligible PSA 138 A˚ 2 metabolism NH HN log P 9.60

N HO OH 565

1/ MeO2C t 2 5–6 h (iv) V 0.6 VERTEPORFIN F – CL 1.7–2.0 Photosensitizer MeO2C pb 91% Mwt 794.8 ur <0.01% PSA 184.6 A˚ 2 log P 7.38 N

NH HN

CO2H

MeO2C

1/ HN HN t 2 3–5 h V 0.3 PLERIXAFOR F 3% CL 1.3 α-Chemokine antagonist, N NH pb 58% Mwt 502.8 immunostimulant; no HN N ur 70% PSA 78.7 A˚ 2 metabolism log P −0.82 NH NH

Index

Bold page numbers = tabulated PK data

a acetylcholinesterase inhibitors 245, 334, 852 A 418 399, 420 abacavir 438 acetylcholinesterase reactivators 398, 399 abanoquil 425 acetyl-CoA 15, 145 abecarnil 299 N-acetylcysteine 99, 162, 339 abiraterone 483 acetylenes 40 abortifacients 490, 539, 541 N-acetylhomocysteine 162 Abraham, Edward P. 522 L-acetylmethadol 165, 237 absorbtion of drugs 14 N-acetylprocainamide 216 ABT-263 365 acetylsalicylic acid 164, 349, 497, 512 ABT-279 345 acifran 510 ABT-761 194 acipimox 70, 398 ABT-869 371 acitretin 153 acadesine 428 acivicin 160 acamprosate 203, 204 acne 152, 153, 481 acarbose 81 ACNU (nimustine) 69 ACE inhibitors 99, 162, 335–340, 352 ACP-103 257 acebutolol 324 acridines 413, 416, 420 acecainide 216 acrivastine 145, 231 aceclofenac 506 acrolein 55, 205 acefylline 441 acromegaly (excessive growth) 360 acemetacin 503 actisomide 238 acenocoumarol 60, 143 active transport of drugs 15, 16 acepromazine 305 active tubular secretion 15 acesulfame 208, 434 acute coronary syndrom 366 acetals 138 acyclovir 437 acetamidoeugenol 42 N-acyl amino acids 147 acetamidoﬂuorene 133 N-acylcyanamides 146 acetaminophen (paracetamol) 84,92 acylguanidines 122, 123 – metabolism 82 acylhydrazines 137 acetazolamide 451, 457 N-acylsulfonamides 146 acetohexamide 37, 139, 458 N-acylureas 193 acetophenone 59 adamantyl group 37 4-(acetylamino)antipyrine 181 adapalene 152 acetylcholine 118, 393 adefovir dipivoxil 210, 443 acetylcholinesterase 118 adenosine 436

adenosine A1 agonists 438 alfacalcidol 489 adenosine A1 antagonists 442 alfentanil 243 adenosine A2A agonists 437 alfuzosin 425 adenosine A2A antagonists 245, 442 alinidine 126 adenosine deaminase inhibitors 444 aliphatic amines 107–117 S-adenosyl-L-methionine 15, 436 aliskiren 168, 349, 357 adimolol 48, 327 alizapride 218 adinazolam 471 alizarin 89, 495 adjunct antineoplastics 254, 367 alkanes 35 adrafinil 146, 157 alkenes 40–44 adrenaline 3, 267 alkyl bromides 53 adrenaline receptors 225 alkyl chlorides 51, 52 adrenergic agonists 273, 281–283 alkyl fluorides 49–51 α2-adrenergic agonists 126, 130, 275 alkyl groups 35 β3-adrenergic agonists 24, 281 alkyl sulfonates 54, 206 α1-adrenergic antagonists 278, 279, 416, alkylating agents 49–56, 206, 300 425, 426 alkynes 40 α2-adrenergic antagonists 125, 299, 380 allergic rhinitis (hay fever) 225–227, α-adrenoceptor antagonists 246 252–258; see also antipruritics, histamine β-adrenoceptor antagonists 195, 320–328 H1 antagonists adrenocortical steroids 477–481 allopurinol 439 adverse drug reactions 17–20 allylamine, pKa 110 afatinib 373 allylbenzenes 42 aflatoxines 41 alminoprofen 499 afloqualone 50, 136, 419 almitrine 41, 253 AFN-1252 171 almokalant 326 AG-1343 351 almorexant 288 AG-14699 300 almotriptan 293 AG-337 418 alogliptin 342, 435 agomelatine 48, 275 alosetron 381 agranulocytosis 18, 19, 173 alovudine 432 ajmaline 298 alphaxalone 483 alacepril 167, 339 alpidem 52, 410 alafosfalin 209, 211 alprazolam 470 alanine, as solubility enhancer 166, 167 alprenolol 320, 322 alatrofloxacin 167, 516 alprostadil 539 albaconazole 389 altretamine 398 albendazole 385 alvimopan 168, 239, 330 albendazole sulfoxide 61, 188, 385 Alzheimer’s disease 245, 297, 353, 355, 417 albumin 6 α-amanitin 347 albuterol 284 amantadine 37, 115 alclofenac 499 ambrisentan 151 alcohol dehydrogenase inhibitors 379 ambroxol 117, 136 alcohols 71–81 amdinocillin 526 – acidity 40 amebicides, see antiprotozoals – prodrugs 164, 186, 213, 214 ameltolide 344 alcoholism 194, 204 amezinium 407 alcuronium 300 AMG 706 366 aldehyde dehydrogenase inhibitors 194 amides 166 aldehydes 138 – as prodrugs 114, 167 aldose reductase inhibitors 153, 163, 178, amfenac 500 201, 502 amfepramone 270 aldosterone antagonists 487 amfonelic acid 516 alendronic acid 211 amidines 120 Index 569 amidopyrine 181 AMPA antagonists 404 amifampridine 398 amperozide 240 amiflamine 273 amphetamine 270 amifostine 214 amphetamines 267 amikacin 79 N-Lys-amphetamine 270 amiloride 123, 130, 408 amphotericin B 561 amineptine 313 ampicillin 204, 526 amines 107, 133, 225 ampiroxicam 186 – basicity 40, 110 amprenavir 214, 351 – metabolism 110–114 amrinone 406 – prodrugs 112–114, 167, 187 amsacrine 416 – rates of N-dealkylation 111–114 amylocaine 215 aminoacetonitrile, pKa 110 anabolics 434 amino acid conjugation 15 anacetrapib 177 amino acids 147, 157–163 anaerobic organisms 378 N-(aminoalkyl)benzamides and -benzoates anagrelide 131 215–224 analeptics, see CNS stimulants aminoalkylindoles 291–300 analgesics 4-aminoantipyrine 181 – narcotic 149, 227, 228, 237, 239, 243, 251, aminobenzenesulfonamides 21, 450 274, 278, 329–334 2-aminobenzoic acid 498 – non-narcotic 84, 85, 126, 153, 181, 211, 4-aminobiphenyl 133 235, 236, 270, 276, 305, 316, 330, 403, 4-aminobutyric acid, see GABA 405, 455, 456 9-aminocamptothecin 423 anastrozole 184, 390 amino carboxylic acids 147, 157–163 andarine 170 6-aminocaproic acid 157 androgen receptor modulators 170, 179 aminoglutethimide 136, 196 androgens 477, 485, 486 aminoguanidine 128 anesthetics aminoglycoside antibacterials 78–81 – inhalation 53 6-aminohexanoic acid 157 – iv 84, 116, 198, 199, 243, 281, 471 aminoisobutyric acid 347 – local 77, 84, 215, 216, 224, 236, 341–344, 6-aminopenicillamic acid 522, 523 483 aminopeptidase inhibitors 156 angina pectoris 66, 320 aminopeptidases 166 angioedema 359 aminophenols 82 angiotensin 335 aminopterin 551 angiotensin converting enzyme (ACE) 335; 4-aminopyridine 395, 398 see also ACE inhibitors aminopyrine 173 angiotensin II antagonists (sartans) 335, 5-aminosalicylic acid 511, 512 543–547 amiodarone 17, 54, 261 angiotensinogen 335 amisulpride 106, 218 anidulafungin 359 amitriptyline 101, 312 anilides of glycine 341–346 amlexanox 495, 507 aniline 133 amlodipine 108, 165, 449 anilines 133–136 ammonium chloride (for urine acidification) aniracetam 172, 174 269 anorexics (appetite suppressants) 125, 251, ammonium salts 107, 118 268, 270–273, 280 amobarbital 198 anseculin 247 amocarzine 194, 201, 371 antabuse (disulfiram) 194, 202 amodiaquine 414, 420 anthelmintics (vermicides) amorolfine 273 – cestodes 86, 264 amosulalol 285 – nematodes 97, 124, 127, 194, 250, 385, amoxapine 318 386, 562 amoxicillin 526 – schistosoma 74, 158, 183, 287, 288, 496 570 Index

anthelmintics (vermicides) (contd.) antibacterials – trematodes 57 – aminoglycosides 79–81, 129 anthracene 47 – amphenicols 78 anthracyclines 492–495 – ansamycins 562, 563 anthranilic acid 498 – antifolates 404, 405, 450 anthraquinones 495, 496 – carbamates 176 antiacetylcholinesterase agents 118 – diaminopyrimidines 404, 405 antiacne agents 152, 153, 481 – dyes 62, 512 antiadrenal agents 56 – β-lactams 522–537 antiadrenergics 117 – lincosamides 78 antiallergics 247, 440, 478, 481, 495, 507, – macrolides 557, 559–563 510, 515 – nitrofurans 183 antialopecia agents (hair-growth stimulants) – other 116, 160, 161, 210, 211, 317, 356, 407 384, 399, 417 antiamyloidogenic agents 204 – peptides 361 antiandrogens 170, 179, 481 – quinolonecarboxylic acids 514–521 antianginals – sulfonamides 21, 450, 458, 459 – β-blockers 321–328 – sulfones 87 – calcium antagonists 227, 229, 474 – tetracyclines 492–495 – carnitine palmitoyltransferase inhibitors antibacterial adjunct 162 230 antibiotic resistance 523 – nitrous oxide precursors 66, 76, 401 anticholinergics 118, 150, 221–223, 230, – phenethylamines 276, 277, 286 233, 238, 303, 304 – piperazines 252 anticholinesterase agents 118 antiangiogenics (vascular growth anticoagulants 127, 142, 143, 177 suppressants) 366, 371, 372 anticonvulsants, see antiepileptics antianxiety agents, see anxiolytics antidepressants antiarrhythmics – bicyclics 159, 228, 231, 270, 275, 276, 280 – adenosine A1 antagonists 438 – hydrazines 400 – alkylamines 182, 233, 236, 238, 241, 257, – other 176, 216, 217, 236, 237, 271, 273, 259, 261, 263, 285, 298, 307, 313, 345, 281 422, 435 – pyrrolidones 175 – amidines 125 – tetracyclics 125, 245, 247, 249, 266, 293, – ammonium salts 117, 222 317, 318, 471 – β-blockers 321–328 – tricyclics 230, 234–236, 247, 251, 259, – calcium channel blockers 277, 474 306, 310–314, 317, 406 – guanidines 128 antidiabetics – phenethylamines 276, 277, 279, 286 – biguanides 131 – potassium channel blockers 117, 263, 463 – carboxylic acids 150–152, 163, 510 – sodium channel blockers 216, 217, 220, – DPPIV inhibitors 8, 23, 273, 288, 342, 224 345, 346, 355, 435, 443 antiarteriosclerotics 399 – other 77, 78, 128, 129, 458 antiarthritics 79, 89 – sulfonylureas 462–464 antiasthmatics – thiazolidinediones 178, 179 – β2-adrenergic agonists 283, 286 antidiarrheals 237, 239, 241 – leukotriene D4 antagonists 422, 440, 509, antidiuretics 360 511 antidotes – lipoxygenase inhibitors 194, 495 – for cholinesterase inhibitors 398, 399 – mast cell degranulation blockers 510 – for curare 85, 190 – methylxanthines 440, 441 – for ethylene glycol 379 – other 224 – for heavy metals 158, 159, 162 – PDE4 inhibitors 151 – for methanol 379 – steroids 478, 480 antidyskinetics (tremor suppressants) 217, – thromboxane A2 antagonists 150 287, 401 Index 571 antiemetics (nausea suppressants) – calcium channel blockers 277, 279, – dopamine antagonists 217–219, 244, 260, 446–449, 473, 474 304, 307, 308 – dihydropyridines 446–449 – histamine H1 antagonists 252–254, 303 – dopamine agonists 272 –5-HT3 antagonists 219, 223, 381 – guanidines 126–128, 130, 400 –NK1 antagonists 265, 266 – hydrazines 404, 419 – THC analogs 86 – indole alkaloids 298, 299 antiepileptics – other 159, 403, 407, 418, 488 – acylureas 195 – potassium channel openers 174, 407 – alcohols 74 – prostaglandin analogs 540 – amides 148, 162, 175, 354 – quinazolines 425, 426 – barbiturates 197 – renin inhibitors 357 – benzodiazepines 466–476 – sulfonamides 452–454 – carbamates 177, 189, 190, 404 antihyperthyroids 182, 201, 434 – carboxylic acids 148 antihypoglycemics 452 – dibenzazepines 316 antihypotensives 273, 282, 285, 407 – GABA analogs 160, 161 antiinflammatories, non-steroidal, see – GABA reuptake inhibitors 240 NSAIDs – imides 177, 178, 196 antiinflammatories, steroidal 477–481 – sodium channel blockers 405 antileprotics 87 – steroids 483 antileukemics, see antineoplastics – sulfamates 95 anti-Lewisite (dimercaprol, BAL, – sulfonamides 457, 458 2,3-dimercaptopropanol) 98 antiestrogens 263 antilipemics 86, 154, 155, 161, 205, 398, 510, antifibrotics 406 549, 550 antifolates 404, 405, 408, 409, 450, 551–553 antimalarials, see antiprotozoals antifreeze agents 76 antimetabolites 428 antifungals antimigraine agents 95, 148, 159, 248, 253, – alcohols 76, 86 (phenol) 258, 291–296, 354 – amines 116, 273 antimitotic agents, see antineoplastics – amino acids 160 – guanidine 127 antimony-containing drugs 158 – N-hydroxypyridones 406 antimuscarinics 118, 232 – imidazoles 387, 388, 391 antimycotic, see antifungals – peptides 359 antineoplastics – polyenes 561 – alkylating agents 49–56, 141, 206, 300, – triazoles 387–392 398 antiglaucoma agents 122, 126, 246, – anthracyclines 492, 493 321–328, 380, 385, 457, 540, 541 – antifolates 408, 409, 551–553 antigonadotropins 485 – antimitotics 291, 297, 298, 375, 554–556 antigout agents 476, 510 – apoptosis inducers 89, 194, 355, 365, 367 antihemorrhagics (hemostatics) 148, 157, – epipodophyllotoxins 89, 90 160, 182, 205 – epothilone analogs 564 antihistaminics, see histamine antagonists – farnesyltransferase inhibitors 476 antihyperlipemics, see antilipemics – histone deacylase inhibitors 156, 360, 366, antihypertensives 367 – ACE inhibitors 99, 162, 335–340, 352 – hormonal 170, 179, 196, 263, 357, 358, – α1-adrenergic antagonists 125, 244, 248 483, 486, 487 – α2-adrenergic agonists 126 – kinase inhibitors 22, 217, 258, 366, 368, – angiotensin II antagonists 543–547 369, 371–375, 412 – arylethanolamines 285, 286 – matrix metalloproteinase inhibitors 352, – aryloxyacetic acids 151, 155 353, 371, 505 – aryloxypropanolamines 248, 276, 320–328 – N-nitrosoureas 68, 69 – benzothiadiazines 452, 453 – nucleoside analogs 418, 428–439, 444 572 Index

antineoplastics (contd.) – factor Xa inhibitors 170, 176, 177, 266, – other 117, 157, 160, 194, 252, 255, 262, 363, 367, 370 288, 300, 354, 356, 357, 366, 370, 372, – NSAIDs 500; see also NSAIDs, salicylates 374, 375, 381, 386, 390, 402, 461, 505, – other 180, 247 509, 558 – platelet aggregation inhibitors 265, 366, – platinum complexes 158 439, 539, 540 – radiosensitizers 383, 564, 565 – platelet glycoprotein IIb/IIIa blockers – topoisomerase inhibitors 299, 416, 423, 265, 361, 362 424, 496, 516 – thrombin inhibitors 363, 364 – triazenes 64, 65, 382, 507 – thromboxane antagonists 149, 150, 156, antiobesity agents 152, 171 542 antiosteoporotics 88, 210, 260–263, 353 – thromboxane synthase inhibitors 149, antiparkinsonians 380, 510 – adenosine A2A antagonists 442 – vitamin K antagonists 142, 143 – alkylamines 115 antithyroids 261 – COMT inhibitors 83, 85, 86 antitumor agents, see antineoplastics – diarylalkylamines 233, 257, 303 antiulceratives – dopamine agonists 274, 275, 294–296 – histamine H2 antagonists 101, 132, 264, – dopamine precursors 83, 159 377, 380–382, 402 – dopamine reuptake inhibitors 251 – muscarinic M1 antagonists 313 – MAO inhibitors 271 – other 163, 407 antiplatelet agents 162, 465; see also platelet – prostaglandin analogs 541 antiprotozoals – proton pump inhibitors 104, 370, 396, – ameba 85, 382, 383, 417 409, 410 – giardia 183, 382 antiurolithics 439; see also uricosurics, – leishmania 127 hyperuricemia – malaria 62, 94, 95, 97, 131, 211, 233, 413, antiussives (cough suppressants) 221, 248, 414, 417, 420–422 260, 261, 281, 288, 329–334, 345 – pneumocystis 127, 141, 157 antivertigo agents 401; see also motion – toxoplasma 141, 405 sickness – trichomonas 382, 383 antivirals – trypanosoma 127, 157, 384 – CCR5 antagonists 253, 382 antipruritics 77, 158, 254, 255, 304, 305; see – hepatitis 351, 436 also hay fever, histamine H1 antagonists – HIV 200, 240, 253, 317, 350–352, 354, antipsoriasis agents 153, 489, 509 369, 382, 405, 516 antipsychotics – neuraminidase inhibitors 122, 129, 160 – benzamides 217, 218 – nucleoside analogs 209–211, 428–438, – butyrophenones 241, 242 443, 444 – other 240, 241, 244–247, 249, 250, 274, – other 115, 127, 143, 190, 385, 418, 425 287, 309, 311, 318, 319 – reverse transcriptase inhibitors 294, 317 – phenothiazines 301, 304–308 anxiolytics (fear suppressants) antipyretics, see antiinflammatories – arylpiperazines 249, 318 antipyrine 181 – benzodiazepines 466–476 antirheumatics, see rheumatoid arthritis – carbamates 189, 190 antirickettsials 78 – other 125, 199, 234, 256, 266, 299, 306, antiseizure agents, see antiepileptics 370, 391, 410, 426 antiseptics 82, 87, 132 apalcillin 526 antiseptic surgery 82 apazone 4 antisickling agents 151, 509 apixaban 177 antispasmodics 88, 117, 219–222, 227, 230, aplastic anemia 18 232, 257, 261, 287 apomorphine 287, 334 antithrombocythemics 131 apoptosis inducers 89, 194, 355, 365, 367 antithrombotics appetite stimulants 86, 482 – antiplatelet agents 162, 465 appetite suppressants, see anorexics Index 573 apraclonidine 126 asulacrine 416 aprepitant 214, 265 ataluren 508 apricitabine 431 atazanavir 349, 354 aprindine 236 atenolol 3, 320, 326 aprobarbital 198 atherosclerosis 399 aqueous pores 14, 119 atipamezole 380 arabinofuranosylguanine 438 atomoxetine 228 arabinosyl-5-azacytidine 430 atorvastatin 46, 549 arachidonic acid 538 atovaquone 141 arecoline 264 atracurium 290 arene oxides 45 atrasentan 505 arenes 45 atrial fibrillation 81, 330 arenesulfonamides 21, 450–460 atropine (hyoscyamine) 223 argatroban 363 attention deficite hyperactivity disorder 228, L-arginine 129 229 aripiprazole 247 atypical antipsychotics 240, 318, 319 armodafinil 157 auranofin 79 aromatase inhibitors 390 aurothiomalate 158 aromatic hydrocarbons 45 autan 169 aromatic hydroxylation 45 avibactam 182 aromatic thiols 99 avitriptan 248, 294 artelinic acid 94 axitinib 372 artemether 94 azacytidine 430 artemisinin 95 azanidazole 384 artemotil 97 azapropazone 180, 418 artenimol 97 azasetron 219 artesunate 94 azatadine 254, 315, 393 arthritis, see antiarthritics, rheumatoid azathioprine 439 arthritis AZD 6140 439 articaine 164, 344 AZD 6244 372 articainic acid 344 azelastine 258 artificial sweeteners 77, 79, 115, 205, 434 azetidine, pKa 110 arundic acid 148 azides 58, 133 526 arylacetic acids 497–506 azidocillin 58, 546 arylalkylamines 225–266; see also azilsartan 182 phenethylamines azimilide 108, 2-(arylamino)benzoic acids 498 aziridine, pKa 110 aryl bromides 53 aziridines 54 561 aryl chlorides 52 azithromycin 108, 527 aryl fluorides 50 azlocillin N-arylhydroxylamines 60, 135 azo compounds 62 3-aryloxy-2-hydroxypropylamines 320–328 azoles, see imidazoles, triazoles arylpropionic acids 303, 497–503 azomycin 378 454 507 arzoxifene 260 azosemide , 534 ASA404 505 aztreonam 208, ascaridole 97 ascorbic acid (vitamin C) 77 b asenapine 318 baclofen 160, 272 asimadoline 278 bacterial fatty acid biosynthesis inhibitors asoprisnil 489 171 aspirin 164, 349, 497, 512 bacterial infections, see antibacterials astemizole 226, 258 bafetinib 368 Astra 341, 396 BAL (dimercaprol) 98 astrocyte modulating agents 148 balofloxacin 519 574 Index

balsalazide 62, 512 benzylisoquinolines 269 bambuterol 284 benzylpenicillin 204, 522, 527 bamethan 35, 83, 282 bepotastine 257 bamifylline 442 bepridil 136, 227 barbital 193, 199 beraprost 540 barbiturates 17, 193, 197–199 besifloxacin 519 barnidipine 449 besipirdine 403 basic drugs, see amines, amidines, etc. beta-adrenergic, see β-adrenergic batimastat 352 beta-blockers 320 BAY 59-8862 556 betahistine 393, 401 BAY-129566 505 beta-lactamase inhibitors 182, 524 Bayer 193, 215, 446, 498 beta-lactams 522–537 bazedoxifene 261 betamethasone 478 BB 83698 356 betamipron 162 bbb penetration 16 betaxolol 39, 93, 325 BCH-4556 430 bethanidine 128 Bcl-2 inhibitors 365, 375 betrixaban 367 BCNU 69 bevantolol 276, 327 beclobrate 154 bevirimat 491 beclomethasone dipropionate 478 bexarotene 509 befloxatone 176 bezafibrate 154 benazepril 164, 339 bezitramide 239 bencyclane 236 BG 9928 442 bendamustine 56, 151 biapenem 524 bendazac 502 BIBW 2992 373 bendroflumethiazide 452 bicalutamide 170, 184 benign prostatic hyperplasia 278, 279, 416 bicifadine 270 benoxaprofen 144, 501 bidisomide 238 benperidol 242 bifemelane 260 benproperine 260 bifeprunox 245 benserazide 137 biguanides 122, 123 benzalkonium 118 bilastine 155, 256 benzamides 215 biliary excretion 15 benzarone 88 bilobalide 95 benzbromarone 53, 88 bimatoprost 540 benzene 47 bioactivation, carcinogens 45, 133, 135 benzenes, see arenes bioavailability 6, 14 benzidine 133 bioisosteres benzimidazoles 61, 378, 385, 386 – of carboxylic acids 146 benznidazole 384 – of esters 393 benzocaine 215 –ofphenols83 benzoctamine 306 – of thioethers 100 benzodiazepine agonists 299 biological stains, see dyes benzodiazepine antagonists 471 biopterin 408 benzodiazepines 60, 169, 466–476 biotin 162 benzoic acid 145, 511 biperiden 233 benzoic acids 497, 506–513 bisacodyl 207 benzonitrile 59 bisaramil 224 benzphetamine 273 Bischler–Napieralski reaction 269 benzpyrene 47 bis(2-chloroethyl)sulfide 54 benzthiazide 102, 452 bisnorbiotin 162 benzydamine 236 bisoprolol 325 benzylamine, pKa 110 bisphenol A 86 benzylamines 116, 117 bisphosphonates 210–212 Index 575 bisquaternary ammonium salts 118, 119 brompheniramine 231 bizelesin 300 bronchodilators Black, James 320 – ammonium salts 222 bleeding, see anticoagulants – PDE4 inhibitors 170 blonanserin 250 – phenethylamines 280, 281, 283–286 blood clearance 7 – xanthines 440–442 blood–brain barrier 16 brostallicin 357 BMS-184476 555 brotizolam 475 BMS-204352 200 Brotzu, Giuseppe 523 BMS-214662 476 bucolome 197 BMS-275183 555 budesonide 480 BMS-317180 356 budiodarone 261 BMS-564929 179 budipine 257 BMS-708163 353 buflomedil 242 boceprevir 351 buformin 131 BOF-4272 445 bufuralol 286 bone resorbtion inhibitors 210–212 bumetanide 454, 508 bopindolol 324 bunazosin 426 boronic acids 354, 355 bupivacaine 344 bortezomib 354 bupranolol 39, 321 bosentan 407 buprenorphine 334 Bossert, Friedrich 446 bupropion 281 bosutinib 374, 412 burimamide 101 bradycardics 263 buserelin 347, 357 249 bradykinin B2 antagonists 359 buspirone B-raf inhibitors 370 Buss, Carl Emil 497 55 brasofensine 251 busulfan , 206 199 breathing, see respiratory stimulants butabarbital 198 brequinar 154, 521 butalbital bretylium 117, 118 butanethiol 98 brimonidine 126 butanol 98 307 brinzolamide 457 butaperazine 116 british anti-Lewisite (dimercaprol) 98 butenafine 199 brivanib 372 butethal 157 brivanib alaninate 372 buthionine sulfoximine 325 brivaracetam 173, 175 butofilolol 331 brivudine 53, 433 butorphanol 313 brodimoprim 404 butriptyline brofaromine 259 tert-butylamine, pKa 110 bromazepam 394, 469 butylmercaptan 98 222 bromazine 235, 393 butylscopolamine 222 bromfenac 500 butylscopolammonium 118, bromhexine 53, 116 O-benzoylmepindolol 324 γ bromide 173 -butyrolactams 173–176 bromine 53 butyrophenones 241, 242, 256 bromisovalum 193, 195 bromoarenes 53 c bromobenzene 59 cabazitaxel 555 bromocriptine 296 cabergoline 295 bromodiphenhydramine 235 cadralazine 187, 404 bromopride 217 caffeine 440, 451 bromotetrandrine 290 calcifediol 488 bromovinyluracil 433 calcipotriol 489 bromperidol 241 calcitriol 488, 489 576 Index

calcium channel blockers carcinoid syndrom 360 – arylalkylamines 227, 229, 276, 277, 279 cardiac arrhythmias 17 – dihydropyridines 446–449 cardiac depressants, see antiarrhythmics – piperazines 241, 253, 345 cardiac glycosides 81 calcium disodium edetate 158 cardiac myosin activators 372 calcium mimetics (agonists) 229 cardioprotectives 130, 131, 196, 428 calcium regulators 212, 488 cardiotonics 182, 276, 324, 400, 406, 410, calcium sensitizers 411 411, 425, 487 calomel (Hg2Cl2) 451 cardiovascular agents 278 camazepam 472 carebastine 256 Camptotheca acuminata 415 carfecillin 529 camptothecin 415 carﬁlzomib 352 cancer, see antineoplastics carglumic acid 150 candesartan 546 carindacillin 529 candesartan cilexetil 186, 546 Carini, David J. 543 canertinib 374 cariporide 130 cannabinoid antagonists 171, 234 carisbamate 190 canrenone 488 carisoprodol 189 capecitabine 187, 432 carmegliptin 288, 342 capillary protectants, see vasoprotectants carmofur 434 capravirine 190 carmoxirole 248 capreomycin 1A 564 carmustine 69 capromorelin 356 carnitine 161 captopril 99, 162, 167, 335, 336, 339 carnitine palmitoyltransferase inhibitors 230 carazolol 326 caroverine 227 carbamates 187–191 carprofen 501 carbamazepine 17, 310, 316 carteolol 323 carbamazepine-10,11-epoxide 310, 316 carticaine 344 (2-carbamoylphenoxy)acetic acid 512 carumonam 534 carbamoyl phosphate I synthase activators carvedilol 326 150 casopitant 192, 266 carbapenems 523, 529–537 caspofungin 359 carbenicillin 204, 528, 529 catecholamines 83, 267, 268 carbetapentane 221 catechol-O-methyltransferase (COMT) 82, carbidopa 83, 137, 159 83, 268 carbimazole 181, 201 catechols (1,2-dihydroxybenzenes) 82, 268 carbinoxamine 235, 393 cathartics, see laxatives carbocromen 278 cathepsin K inhibitors 353 carbohydrates 71, 78–81 caustics (keratolytics) 148 carbonates 186 Caventou, Joseph Bienaime´ 413 carbonic anhydrase inhibitors 385, 451, 454, CB 10-277 65, 507 457, 458 CCK antagonists 355 carboplatin 158 CCR5 (chemokine 5) antagonists 253, 382 N-(carboxyalkyl)-α-amino acid amides CDK inhibitors 444 335–340 cediranib 373 carboxylic acids 144–163 cefaclor 530 – bioisosteres 146 cefadroxil 530 – metabolism 145 cefamandole 530 carboxylic esters 154, 155, 164 cefatrizine 530 carboxypeptidases 166 cefazedone 532 carbromal 193, 195 cefazolin 532 carbutamide 462 cefcanel daloxate 186, 532 carcinogens 47, 49, 64, 68, 69, 117, 133, 178, cefdinir 533 179, 183, 394 cefditoren pivoxil 535 Index 577 cefepime 535 chloral hydrate 74, 138, 188 cefetamet 535 chlorambucil 52, 56, 151 cefetamet pivoxil 535 chloramphenicol 60, 73, 78 ceﬁxime 534 chlorcyclizine 252 cefmenoxime 536 chlordiazepoxide 466, 467, 474 cefmetazole 532 chlorguanide 131 cefminox 533 chlorhexidine 124, 132 cefodizime 534 chlorinated biphenyls 52 cefonicid 203, 531 chlorine 51 cefoperazone 536 chlorine vs methyl 52 ceforanide 531 chlormadinone 482 cefotaxime 534 chlormequat 51 cefotetan 533 chlormerodrin 451 cefotiam 536 chlormethine 55 cefoxitin 531 chlormezanone 106, 199 cefpimizole 537 2-chloroethylamine derivatives 52 cefpiramide 536 chloromethyl ethers 49 cefpirome 534 p-chlorophenoxyisobutyric acid (CPIB) 154 cefpodoxime proxetil 186, 535 1-(3-chlorophenyl)piperazine 247, 250 cefprozil 530 chloroprocaine 216 cefroxadine 530 chloroquine 4, 113, 413, 414, 420 cefsulodin 532 chlorothiazide 451, 452 ceftaroline fosamil 532 chlorozotocin 69 ceftazidime 534 chlorphenesin 76 ceftibuten 102, 533 chlorpheniramine 4, 71, 231 ceftizoxime 533 chlorphentermine 272 ceftobiprole medocaril 537 chlorproguanil 124, 131 ceftriaxone 536 chlorpromazine 4, 109, 301, 304 cefuroxime axetil 535 chlorpropamide 52, 463 celecoxib 455 chlorprothixene 101, 305 celiprolol 324 chlorquinaldol 417 centchroman 262 chlortetracycline 492, 494 central nervous system, see CNS chlorthalidone 454 cephacetrile 531 chlorzoxazone 200 cephalexin 529 cholecystokinin antagonists 150 cephaloridine 531 choleretics (bile excretion enhancers) 77 cephalosporins 523, 529–537 cholesterol 548 cephalosporin C 523 cholesteryl ester transfer inhibitors 177, 191 cephalothin 531 choline 118 cephapirin 531 cholinergics 85, 118, 190, 191, 264, 399, 420 cephradine 529 cholinesterase, see acetylcholinesterase cerivastatin 550 choriocarcinoma 551 ceronapril 209, 339 chromonar (carbocromen) 278 cetamolol 322 CI 941 496 cetirizine 254 cibenzoline 125 cetrorelix 358 cicaprost 539 cevimeline 264 ciclazindol 125 CGRP antagonists 354 ciclesonide 480 Chain, Ernst Boris 522 cicletanine 403 chelating agents 158, 159, 398, 417, 508 ciclopirox 406 α-chemokine antagonists 565 cidofovir 209, 430 chemokine 5 (CCR5) antagonists 253, 382 cifenline 120, 125 chemotherapeutics, see antineoplastics cilansetron 381 chinchona bark 4, 413 cilastatin 160, 525 578 Index

cilazapril 339 clonazepam 468 cilnidipine 448 clonidine 123, 126 cilomilast 151 clonixin 506 cilostazol 247 clopamide 137, 453 cimaterol 286 clopenthixol 308 cimetidine 17, 101, 377, 381 cloperastine 235 cimetropium 222 clopidogrel 265 cimicoxib 455 cloprednol 479 cimoxatone 176 clorazepic acid 472 cinacalcet 48, 229 clot prevention, see anticoagulants, cinaldipine 448 antithrombotics cinchonine 422, 521 clotiazepam 475 cinchophen 153 clotrimazole 387, 388 cinitapride 219 cloxacillin 528 cinmetacin 503 cloxazolam 473 cinnarizine 50, 253 clozapine 19, 318 cinolazepam 474 CMN 131 396 cinoxacin 515 CMX001 430 cipemastat 352 CNDAC 432 ciprofibrate 144, 154 CNS stimulants ciprofloxacin 17, 514, 517 – amidines 125, 128 ciramadol 73, 276 – benzhydrylamines 313 cisapride 220, 246 – indoles 299 cisplatin 158 – indolones 403 citalopram 184, 234 – phenethylamines 251, 270, 271 citrulline 157 – sulfoxides 157 cizolirtine 235 – xanthines 440 cladribine 436 coagulation factors, see factor Xa inhibitors clamikalant 463 cocaethylene 224 clarithromycin 17, 559 cocaine 215, 224 classic antihistaminics 225; see also cocaine addiction 241 histamine H1 antagonists codeine 91, 108, 269, 332 clavulanic acid 524 coffee 397, 398; see also caffeine clearance 7 COL-3 495 clebopride 219 colchicine 476 clemastine 92, 236 colorectal cancer; see antineoplastics clenbuterol 35, 83, 286 common cold 225 clentiazem 473 compactin (mevastatin) 548 clevidipine 448 COMT inhibitors 83, 85, 86 clinafloxacin 520 congestive heart failure 275, 411 clindamycin 78, 102 conivaptan 376 clinical development 5 conjugation reactions (phase II reactions) clioquinol 417 15 clobazam 474 constipation 329; see also laxatives clobutinol 281 contergan 189 clocapramine 168, 240, 314 contraceptives 262, 481–486, 490 clodronic acid 212 contrast agents 72, 75, 76 clofarabine 50, 436 coronary artery disease 548 clofazimine 417 coronary vasodilators, see vasodilators clofibrate 154 corticosteroids 477–481 clofoctol 87 cortisol 479 clomethiazole 51, 57 cortisol biosynthesis inhibitors 196 clomiphene 262 cortisone 477, 479 clomipramine 314 cotinine 175, 395, 402 Index 579 cough suppressants, see antiussives cytochrome P450, see CYP coumarin 141 cytotoxic drugs, see antineoplastics COX inhibitors 455, 498 460 CP 14304 d 217 CPI-1189 DA-8159 443 154 CPIB dabigatran etexilate 121, 363 127 creatine , 394 dacarbazine 65, 382 127 creatinine , 394 daidzein 88 cremophor EL 554 dalfampridine 398 369 crizotinib dalfopristin 563 cromakalim 3, 174 daltroban 156 cromoglicic acid 510 danazol 485 cromolyn 510 dantrolene 108, 183 CS-758 389 danusertib 368 curare 289 dapagliflozin 79 curcumin 89 dapiprazole 246 cyamemazine 305 dapotum 308 cyanide 184 dapoxetine 48, 228 cyanoguanidines 202, 400 dapsone 87, 134 cyclacillin 526 darbufelone 85 cyclamate 37, 115, 205, 208 darexaban 367 cyclic peptides 347, 358–361, 563, 564 darifenacin 238, 278 cyclin-dependent kinase inhibitors 258 darinaparsin 355 cyclizine 226, 252 darodipine 448 cyclobarbital 197 darunavir 352 369 cyclobenzaprine 311 dasatinib 493 cyclofenil 87 daunorubicin 492, cycloguanil 405 DDT 52 cycloheptane 100 dealkylation cyclohexane 100 – of amides 169 1,2-cyclohexanediol 141 – of amines 110–114 –ofethers92 1,4-cyclohexanediol 141 – of lanosterol 387 cyclohexanes 37 debrisoquin 128 cyclohexanol 141 decitabine 430 cyclohexanone 141 decongestants 124, 126, 280, 282 cyclohexylamine 115 DEET 169 cyclooxygenase (COX) 538 deferasirox 508 cyclooxygenase inhibitors 455, 456, deferiprone 398 497–513 deferoxamine 357 cyclopentane 91, 100 deflazacort 481 55 cyclophosphamide 52, dehalogenation 53 cyclopropylamine, pKa 110 dehydrogenase inhibitors 194 cyclopropylmethyl group 39, 93 deiodination 53 160 cycloserine delapril 338 358 cyclosporine delavirdine 294, 425 CYP-inhibition/induction 16, 17, 394, demeclocycline 494 395 dementia 217 cyproheptadine 254, 314, 393 4-demethoxydaunorubicin 493 cyproterone acetate 481 demexiptiline 313 cysteine 162 demoxepam 467, 474 cystemustine 69 denaverine 165, 221 cystic fibrosis 508 2-deoxy-2-methylenecytidine 431 cytarabine 432 2-deoxyguanosine 437 580 Index

deprenyl 271 2,6-dichlorophenol 126 deramciclane 234 dichlorphenamide 454 N-desalkylflurazepam 469 dichlorvos 74 des-ciclesonide 480 diclofenac 47, 505 desethylchloroquine 113, 414 dicloxacillin 528 desferrioxamine 357 dicoumarol 143 desglymidodrine 167, 285 dicyclomine 221 desipramine 112, 114, 134, 311 dicycloverine 221 desloratadine 114, 255, 315, 393 didanosine 435 desmethylfluoxetine 112, 228 dienogest 184, 486 N-desmethylimatinib 112, 396 diet, see anorexics desmethylsibutramine 112 diethylamine, pKa 110 O-desmethylvenlafaxine 276 5,5-diethylbarbituric acid 193 desmopressin 360 diethylcarbamazine 192, 194 desogestrel 140, 484 diethylcathinone 270 desoxypipradrol 229 diethylpropion 270 detergents (disinfectants) 82, 87, 118 diethylstilbestrol 87 detoxification 18 diethylthiomethylcarbamate 194 development of drugs 13 difenoxin 239 dexamethasone 17, 50, 478 diflomotecan 424 dexmedetomidine 378, 379 difloxacin 517 dexrazoxane 172, 196 diflunisal 513 dextromethorphan 331 difluorodeoxyuridine 431 dextromoramide 237 difluoroethylamine, pKa 110 dextrorphanol 331 digitalis 81 dezocine 274 digitoxin 81, 451 DG-051 260 digoxin 81 diabetes, see antidiabetics dihydroazacytidine 430 diabetic neuropathy 163, 178 dihydrobiopterin 408 diabetic retinopathy 375 dihydrocodeine 332 diacerein 89, 495, 513 dihydroergocristine 296 diacetolol 324 dihydroergocryptine 296 diacetylmorphine 333 dihydroergotamine 296 diacetylrhein 89, 495, 513 dihydroergotoxine 297 diagnostic aids 401, 508 dihydrofolate reductase inhibitors 408, 409, diagnostic dyes, see dyes 551–553 diamines 109, 119 dihydroorotate dehydrogenase inhibitors 20, 2,4-diaminoanisol 133 169 3,4-diaminopyridine 398 dihydropyridines 60, 446–449 diaphoretics (sweating inducers) 380 dihydrotachysterol 488 diazepam 93, 169, 468, 471 dihydroxybenzenes 82, 83 diazepinomicin 317 1,2-dihydroxycyclohexane 141 diazomethane 64 diloxanide furoate 85 diazonium salts 64 Dilthey, Alfred 193 diazoxide 452 diltiazem 17, 165, 446, 474 dibekacin 80 dimercaprol (British anti-Lewisite, dibenzazepines 310–317 2,3-dimercaptopropanol) 98 dibenzepin 317 dimethadione 177 dibromoanthranilic acid 117 dimethindene 232 1,2-dibromoethane 49 4-dimethylaminoazobenzene 133 dichloroacetic acid 148 dimethylamino group 109–112 dichlorobenzene 59 4-dimethylaminostilbene 133 2,6-dichlorobenzaldehyde 130 2,6-dimethylaniline 341, 343 2,6-dichlorobenzylalcohol 130 dimethylcysteine 99, 159, 339 Index 581 dimethylether 100 dopamine antagonists 217, 240–242, 244, dimethyl fumarate 149 245, 260 dimethylnitrosoadamantane 115 dopamine DA2 agonists 248 N-(2,6-dimethylphenyl)glycinamides 341 dopamine D2 agonists 274, 275 dimethylsulfide 100 dopamine D2 antagonists 217–219, 240, dinoprostone 539 250 dioxin (tetrachlorodioxin) 52 dopamine D3 antagonists 27, 218 dipeptidylpeptidase IV, see also DPPIV dopamine D4 antagonists 246 diphenhydramine 17, 225, 234, 377 dopamine reuptake inhibitors 241, 251, 281, diphenoxylate 239 516 diphenylpyraline 257 dopamine transport blockers 230 dipipanone 237 dopamine–norepinephrine reuptake (S)-diprafenone 325 inhibitors 281 diprophylline 441 dopamine receptors 225 276 dipropyl ether 91 dopexamine 383 dipyrone 181, 203 doranidazole 524 dirithromycin 561 doripenem 457 discovery of drugs 3 dorzolamide 313 disinfectants 82, 87, 118 dosulepin 313 disobutamide 108, 238 dothiepin 101, 289 disopyramide 108, 238 doxacurium doxapram 234 dispersion (London) forces 51 doxazosin 425 disposition of drugs 15 doxefazepam 474 distigmine 399 doxepin 101, 145, 312 distribution, volume of 6 doxercalciferol 489 disulfiram 194, 202 doxofylline 138, 441 ditazol 75 doxorubicin 492 diuretics doxycycline 493 – aldosterone antagonists 487, 488 doxylamine 92, 235 – loop 131, 155, 161, 181, 385 DPPIV inhibitors 8, 23, 273, 288, 342, 345, – mercurial 451 346, 355, 435, 443 – sodium channel blockers 130, 408 droloxifene 263 – sulfonamides 450, 452–455, 457, 463 dronabinol 86 – osmotic 76, 77, 193 dronedarone 261 – other 230, 441 droperidol 242 556 DJ-927 drospirenone 488 431 DMDC drotaverine 287 DMSO 101 drug development 3 505 DMXAA drug discovery 3 DNA gyrase 514 drug–drug interactions 16 DNA gyrase inhibitors 8, 514 drug excipients 77 DNA ligands 357 DTI-0009 438 DNA methylation inhibitors 429 duloxetine 228 dobutamine 276 Duncia, John V. 543 docetaxel 554 DuP 697 456 dofetilide 279 DuPont 543 dolasetron 223 dutasteride 487 Domagk, Gerhard 62, 450 dydrogesterone 482 domperidone 244 dyes 62, 89, 90, 300, 495, 508, 512 donepezil 139, 245 dyes, as antibacterials 62, 512 L-dopa, see levodopa dynorphins 329 dopamine 267, 268 dyphylline 441 dopamine agonists 250, 272, 275, 296 dyskinesia (tremor) 217, 287, 401 582 Index

e enoxacin 17, 517 E-2020 245 enoximone 182 EAA 090 211 enprofylline 440 ebastine 256 ensaculin 247 ebrotidine 132 entacapone 83, 86 ecstasy 275 entecavir 73, 437 edatrexate 552 enterohepatic recirculation 15 edotecarin 375 entinostat 136, 188, 366 edoxaban 367 enzastaurin 375 edrophonium 85 enzymatic activation 18, 19 EDTA 158 epalrestat 153, 201 EF5 384 epanolol 327 efaproxiral 154 eperisone 242 efavirenz 17, 188, 200 ephedrine 280 efegatran 364 epichlorohydrin 49 eflornithine 157 epinastine 316 EHNA 444 epinephrine (adrenaline) 3, 267 Ehrlich, Paul 62 epirubicin 492 eicosanoids 538 eplerenone 96, 488 elcometrine 481 eplivanserin 236 electron-poor alkenes (Michael acceptors) epothilone B 564 19, 155 epoxide hydrolase inhibitors 28 electrophilic metabolites 17–19 epoxides 96 elesclomol 194 epristeride 487 eletriptan 293 eprodisate 203, 204 elgodipine 449 eprosartan 545 eliglustat 279 eptastigmine 191 elimination of drugs 15 erdosteine 162 elinogrel 465 Erdtman, Holger 341 eliprodil 283 erectile dysfunction 299, 442, 443, 539 eltanolone 483 ergocalciferol 488 eltoprazine 134, 250 ergocristine, see dihydroergocristine eltrombopag 140, 153 ergoloid 297 elvitegravir 516 ergosterol 387 elvucitabine 433 ergot alkaloids 291, 296, 297 EMD 87580 106, 123, 130 ergotamine 296 emedastine 258 erlotinib 44, 374, 415 emepronium 230 ertapenem 525 emetics 287 erythrohydroxynonyladenine 444 emtricitabine 138, 431 erythromycin 17, 108, 557, 560 enalapril 335, 336 eslicarbazepine acetate 316 enalkiren 357 esmolol 326 encainide 220 esophageal reflux, see antiulceratives enclomiphene 262 estazolam 470 endopeptidases 166 esters 154, 155, 164 endorphins 329 estradiol 44, 477, 486 endothelin antagonists 151, 369, 407, 408, estramustine 56 458, 509 estriol 486 endralazine 137, 419 estrogen receptor modulators 260–262 enilconazole 388 estrogens 87, 477, 485, 486 eniporide 130 estrone 486 enkephalins 329 ET-743 288 enocitabine 432 etafenoxine 125 enoltasosartan 546, 547 etamiphylline 442 Index 583 etamsylate 203, 205 EXP 6155 544 etanidazole 383 EXP 6803 544 ethacrynic acid 155, 451 EXP 7711 544 ethambutol 116 expectorants 76, 116, 117; see also ethanol 17, 71, 74 mucolytics 86 ethanolamine, pKa 110 ezetimibe ethchlorvynol 44, 74 ezogabine 404 ethers 91 ethinamate 44 f 431 3 -C-ethinylcytidine Fabry disease 279 485 ethinyl estradiol 44, 82, factor Xa inhibitors 170, 176, 177, 266, 363, 485 ethinyl estradiol-3-sulfate 367, 370 485 ethinyl estradiol-17-sulfate fadrozole 390 400 ethionamide 201, falipamil 276 303 ethopropazine famciclovir 443 177 ethosuximide 172, famotidine 122, 132 ethoxybenzene 91 fampridine 398 ethoxybenzenes 91, 92 fantofarone 277 385 457 ethoxzolamide , Farber, Sidney 551 270 ethylamphetamine farnesyltransferase inhibitors 255, 380, 476 N-(2-ethylbutanoyl)urea 193 faropenem 524 ethyl carbamate 188 fasudil 422 116 ethylenediamine 110, fatigue suppression 268 76 ethylene glycol fazadinium 410 ethylenimines (aziridines) 54 fazarabine 430 ethyl ethers 91 FDA 9, 10 196 ethylphenylmalonamide febuprol 73, 77 etidocaine 343 febuxostat 510 etidronic acid 212 felbamate 17, 19, 20, 188, 189 etifoxine 125 felodipine 60, 108, 447 etilefrin 282 femoxetine 251 etintidine 382 fenbufen 150 etizolam 475 fenclofenac 47, 505 etodolac 501 fenclozic acid 504 etofenamate 506 fendiline 229 etofylline 440 fendosal 513 etomidate 380 fenethazine 301 etonogestrel 140, 484 fenfluramine 271 etoperidone 247 fenofibrate 155 etoposide 89 fenoldopam 272 etoricoxib 106, 403, 456 fenoprofen 501 etozolin 161 fenoterol 284 etravirine 184, 405 fenpiprane 71, 232 etretinate 153 fenproporex 271 β-eucaine 215 fenquizone 453 everolimus 559 fenspiride 188, 243 exatecan 424 fentanyl 243 excipients 77 fentiazac 504 excitatory amino acids, see AMPA, GABA, feprazone 180 NMDA fesoterodine 232 excretion of drugs 14, 15 fever, see NSAIDs exemestane 486 fexinidazole 384 exopeptidases 166 fexofenadine 256 EXP 3174 545 fiacitabine 431 584 Index

fialuridine 431, 433 fluoxymesterone 485 fibrates 144, 154, 155, 548 flupentixol 309 fibrin 349 fluphenazine 308 fibrinogen 349 flupirtine 188, 394, 404 fibrinogen antagonists 361 flurazepam 469, 474 fidarestat 178 flurbiprofen 499 fidaxomicin 562 flurithromycin 560 fiduxosin 278 flusoxolol 325 Filehne, Wilhelm 173 flutamide 170 finasteride 487 fluticasone 50, 481 fingolimod 73, 77 flutoprazepam 93, 469 finrozole 390 fluvastatin 17, 549 first-pass metabolism 14, 15 fluvoxamine 17, 140, 236, 272 Fischer, Emil 193 folic acid analogs 551–553 Fischer, Otto 172 folinic acid 552 five-membered lactams 173–176 fomepizole 379, 388 FK506 559 fominoben 345 FK-binding protein 557 formamides 356 flavopiridol 252 formestane 487 flavoxate 88, 164 formoterol 283 flecainide 220 4-(formylamino)antipyrine 181 Fleming, Alexander 522 forodesine 437 fleroxacin 518 fosamprenavir 214, 351 flesinoxan 245 fosaprepitant 214 210 flestolol 195 foscarnet 209, 390 flomoxef 533 fosfluconazole 213, 210 Florey, Howard 522 fosfomycin 209, 339 flosequinan 418, 515 fosinopril 211 flosulide 455 fosmidomycin 209, 179 flovagatran 355 fosphenytoin , 213 84 floxacillin 528 fospropofol 366 flucloxacillin 528 fostamatinib fluconazole 17, 213, 389 fostriecin 214 69 flucytosine 434 fotemustine fludarabine 436 fradafiban 362 fludiazepam 60, 93, 469 Franke, Hans 462 293 flufenamic acid 394, 507 frovatriptan fluindione 142 Fuchs, Joachim 462 486 flumazenil 471 fulvestrant flumezinol 74 fungal infections, see antifungals flumequine 515 fungicides 86 441 flunarizine 41, 50, 253 furafylline flunisolide 480 Furakawa, Y. 543 510 flunitrazepam 60, 468 furegrelate 454 508 flunoxaprofen 501 furosemide , fusidic acid 152, 491 fluocinolone acetonide 480 future of small molecule drugs 9 fluocortolone 481 fluorescein 508 fluorine 49 g 2-fluoroaniline 49 GABA agonists 149, 160, 161, 204, 391 2-fluorophenol 49 GABA receptor modulators 483 1-(4-fluorophenyl)piperazine 250 GABA reuptake inhibitors 240 5-fluorouracil 434 gabapentin 37, 160 fluoxetine 10, 17, 112, 228 gaboxadol 161, 264 Index 585 galantamine 334 – antibacterial 78–81 gallamine 259 – cardiac 81 gallopamil 277 glymidine 458 ganaxolone 483 GnRH agonists 357, 358 ganciclovir 437 GnRH antagonists 358 ganglionic blocking agents 118 gold sodium thiomalate 158 Gardos channel inhibitors 151 gonadotropin agonists 347 garenoxacin 521 goserelin 358 gastric ulcers, see antiulceratives gout suppressants 476, 510 gastrin project 396 gramine 341 gastrointestinal tract 14 granisetron 223 gastroprokinetics 217–220, 246, 355 grapefruit 16, 17 gastroprotectants 141, 541 grepafloxacin 17, 517 gatifloxacin 518 growth hormone 17 Gaucher’s disease 78, 279 growth hormone secretagogues 356 gefitinib 373, 412 Grunenthal¨ 189 gemcitabine 73, 431 guaifenesin 76 gemfibrozil 154, 550 guanabenz 122, 130 gemifloxacin 520 guanadrel 128, 140 genaconazole 389 guanethidine 122, 128 genistein 88 guanfacine 123, 130, 342 gentamicin 80 guanidine 127 gentisamide 512 guanidines 122 gentisic acid 511 guanoxan 128 gepefrine 273 guanylate cyclase stimulators 370 gepirone 249 gut 14 265 gestodene 484 GW597599 gimatecan 423 gyrase inhibitors 514 glaucoma 122, 126 glibenclamide 464 h glibornuride 463 haemo-, see hemo- gliclazide 463 halazepam 169, 470 glimepiride 464 half-life of drugs 6, 15 glipizide 464 halides 49 gliquidone 464 hallucinogenics 116, 264, 275, 295 glisoxepid 464 haloalkanes 49 GLP-1 342 halofantrine 113, 233 glucocorticoids 477–481 halofenate 155 glucose transporter inhibitors 79 halofenic acid 155 glucosylceramide synthase inhibitors 279 haloperidol 17, 72, 139, 241 glucuronidation 15, 146 halothane 53 glutarimides 172, 195, 196 hay fever 225–227, 252–258; see also glutathione 15, 157 antipruritics, histamine H1 antagonists glutathione transferases 15 headache, see migraine, antimigraine agents glutethimide 172, 196 heart failure 372, 509 glyburide 464 heart valve damage 271 glycerin dinitrate 66 heat shock protein 8 glycerol 71, 76 heavy-metal poisoning, antidotes for 158, glycine, as solubility enhancer 114, 166 159, 162 glycine ethyl ester, pKa 110 hedgehog signaling inhibitors 366 glycol 76 hedonal 193 glycopyrrolate 221 helminths (worms), see anthelmintics glycosides hemiacetals 92, 138 – anthracycline 492, 493 hemoglobin 133, 138, 154, 509 586 Index

hemolytic anemia 133, 517 hydrocephalus 94 hemorheologic agents 441 hydrochlorothiazide 452 hemorraghe, see anticoagulants hydrocodone 91, 92, 332 hemostatics 148, 157, 160, 182, 205 hydrocortisone 479 heparin 349 hydroflumethiazide 452 hepatic enzyme inducers 74 hydromorphone 91, 92, 331 hepatitis 351, 436 hydrophilic pores 14, 119 hepatitis C virus protease inhibitors 351 hydrophilicity, effect on PK 6, 7, 71, 72 hepatoprotectants 159, 162 hydroxamic acids 146, 147, 156, 157, 352, hepatotoxicity 18 353 heptabarbital 197 hydroxy acids 157 heptane 91 N-hydroxyamidines 120, 121 herbicides 84, 142, 155, 397, 402 4-hydroxybutyric acid 149 hERG 17 10-hydroxycarbamazepine 316 heroin 164, 333 hydroxychloroquine 420 Hertz, Roy 551 1-hydroxycholecalciferol 489 hexachlorocyclohexane (lindane) 56 3-hydroxycotinine 176, 402 hexachlorophene 87 3-hydroxydihydroquinidine 422 hexanols, solubility 36 hydroxyethylmorphine 332 hexobarbital 41, 197 5-hydroxyindoles 159 hippuric acid 145, 511 hydroxyindolylacetic acid 159 histamine 107, 377, 379, 393 3-hydroxyquinidine 42 histamine agonists 377, 379, 401 hydroxylamines 133, 135 histamine antagonists 377 5-hydroxymethyltolterodine 232 histamine H1 antagonists 155, 225, 227, hydroxynortriptyline 312 230–232, 234–236, 239, 248, 252–258, 303, hydroxytriamterene sulfate 408 304, 312, 316, 402, 442 2-hydroxy-4-trifluoromethylbenzoic acid 511 histamine H2 antagonists 101, 132, 264, hydroxytrimazosin 73 377, 380–382, 402 5-hydroxytryptamine (5-HT), see serotonin histamine H3 antagonists 377 5-hydroxytryptophan 159 histamine H4 antagonists 377 hydroxyurea 192, 194 histamine receptors 225 1α-hydroxyvitamin D2 489 histidine 377 hydroxyzine 254 histone deacetylase inhibitors 156, 360, 366, hyoscyamine (atropine) 223 367 hyperammonemia 149, 150 HIV integrase inhibitors 26, 516 hypercalcemia 212 HIV protease inhibitors 25, 350–352, 354; hypercholesterolemia 548 see also antivirals hypericin 90 HIV-1 maturation inhibitors 491 hyperprolactinemia 274, 294–296 HMG CoA reductase inhibitors 548–550 hypertension 543; see also antihypertensives Hodkin, Dorothy Crowfoot 522 hyperuricemia 445 Hoechst 173, 215 hypnotics Hoffmann, Felix 498 – acyclic ureides 193, 195 Hoffmann-La Roche 466 – alcohols 74 homotaurine 204 – amides 288, 371, 410, 426, 427 hormone replacement therapy 477, 484 – barbiturates 193, 197–199 HSP70 inducers 194 – benzodiazepines 466–476 HSP90 inhibitors 8 – carbamates 188, 189 human ether-a-go-go` related gene 17 – other 74, 161, 235, 236, 380 hycanthone 496 – phenothiazines 303, 305 hydantoins 178, 179, 183 – piperidinediones 195, 196, 199 hydralazine 137, 419 hypoglycemia 452 hydrazines 137 hypolipidemics 87 hydrazones 137 hyponatremia 376 Index 587 hypotensives, see antihypertensives indanazoline 126 hypoxanthine 435 indapamide 453 hypoxia probes 384 indecainide 238 hypoxia-selective antineoplastics 419 indeloxazine 280, 322 indinavir 17, 349, 350 371 i indiplon indirectly acting sympathomimetics 268 ibandronic acid 211 indobufen 500 ibudilast 440 300 ibuprofen 497, 498 indocyanine green ibuproxam 498 indole alkaloids 291–300 502 ibutilide 285 indomethacin 146, 499 ICA-17043 151 indoprofen 244 icatibant 359 indoramin ICI 320 induction of CYP 16 ICL 670 508 infertility 477 iclaprim 405 inflammation, see antiinflammatories icofungipen 160 inhibition of CYP 16 idarubicin 493 injection (parenteral dosing) of drugs 15–17 364 idarubicinol 493 inogatran 435 idazoxan 125 inosine idebenone 141 inotropics, see cardiotonics idoxuridine 433 insect repellents 169 idrapril 352 insecticides 56, 84, 457 idrocilamide 75 in silico drug discovery 9 idronoxil 89 insulin secretagogues 129 ifenprodil 283 insulin sensitizers 151, 152, 178, 179 ifetroban 156 interactions, drug–drug 16 ifosfamide 55 intercalators 492, 496 I. G. Farben 450 intestine 14 299 ilaprazole 410 intoplicine iloperidone 245 intoxication 17–20 iloprost 540 intraocular pressure 126; see also imatinib 112, 368 antiglaucoma agents imidafenacin 237, 380 iodine 53 imidapril 337 iodixanol 75 imidazole 377, 379 iodoquinol 54, 417 imidazoles 377–386 iohexol 54, 75 imidazolines 120 iomeprol 75 imides 146, 172 iopamidol 72, 76 imipenem 525 iopromide 75 imipramine 101, 112, 310, 311 iosimide 76 imipramine N-oxide 112, 311 ipratropium 222 imiquimod 418 ipriflavone 88 immunogenicity 347, 523 iprindole 236 immunomodulators 77, 169, 174, 196, 418, iproniazid 137, 400 436, 439, 559 ipsapirone 249 immunostimulants 565 irbesartan 38, 545 immunosuppressants 55, 153, 154, 358, irinotecan 424 403, 428, 439, 496, 557–559 irofulven 141 incadronic acid 211 iron chelators 357, 508 INCB 9471 253 irreversible tyrosine kinase inhibitors 374 incontinence 220, 232, 238 irritable bowel disease 217, 278, 281, 381 indacaterol 283 irsogladine 407 indalpine 259 isatoribine 436 588 Index

isavuconazole 387, 388 ketotifen 255, 315 isepamicin 80 kidneys 15 isoamyl nitrite 66 kinase inhibitors 422, see also isobutyl nitrite 66 antineoplastics isofagomine 78 kinesin spindle protein inhibitors 374 isofezolac 504 Klarer, Josef 62, 450 isoflavones 88 Knorr, Ludwig 173 isogramine 341 Koenigs, Wilhelm 172 isomazole 410 Kolbe, Adolph Wilhelm Hermann 497 isoniazid 17, 137, 399 Koller, Carl 215 444 isopropylamine, pKa 110 KRN-5500 isoproterenol 83, 284 Kuhn, Roland 310 isoquinolines 269 Kurzrok, Raphael 538 isosorbide 94 KW-6002 442 isosorbide dinitrate 66, 93 isosorbide mononitrate 66, 94 l isosteres, see bioisosteres labetalol 285 isotretinoin 153 Laborit, Henri 301 isovaleramide 148 lacidipine 448 isoxicam 460 lacosamide 354 isoxsuprine 283 lactams 172–183 ispinesib 374 β-lactams 522–537 ispronicline 401 lactic acidosis 131 isradipine 108, 448 lactones 165, 559–562, 564 istaroxime 487 lactulose 78 istradefylline 442 lafutidine 402 itasetron 223 lamifiban 361 itching, see antipruritics lamivudine 431 itraconazole 17, 140, 391 lamotrigine 405 ivabradine 277 landiolol 327 ivermectin 562 laninamivir 129 ixabepilone 96, 564 lanosterol 387 lanreotide 360 409 j lansoprazole lapatinib 374 Jendrassik,´ Ernst 451 laquinimod 461 laropiprant 144, 505 k lasofoxifene 111, 262 KA-672 247 latamoxef 533 kairine 173 latanoprost 541 kairoline A 173 laxatives 77, 78, 130, 207, 264, 539 kanamycin B 80 lazabemide 401 karenitecin 423 LBM 415 356 keratolytics 148 lead discovery 3–8 ketamine 281 lead optimization 13–20 ketanserin 244 lecozotan 245 ketazolam 473 leflunomide 169 ketobemidone 330 lefradafiban 187, 362 ketoconazole 17, 391 lenalidomide 172, 196 3-ketodesogestrel 484 lenampicillin 526 2-ketodoxapram 234 leprostatics 87 ketones 139 lercanidipine 448 ketoprofen 500 lesopitron 249 ketorolac 503 letrozole 184, 390 Index 589 leucovorin 552 lomustine 68 leukemia 206, 493, 509, 551 lonafarnib 255 leukotriene A4 hydrolase inhibitor 260 lonazolac 504 leukotriene D4 antagonists 423, 511 London dispersion forces 51 leukotrienes 538 long QT syndrome 17 leuprorelin 358 lonidamine 502 levallorphan 331 loop diuretics 131, 155, 161, 181, 385 levamisole 127 loperamide 241 levetiracetam 168, 173, 175 lopinavir 350 levobunolol 47, 321, 323 loprazolam 475 levocabastine 239 loracarbef 530 levodopa 83, 159 loratadine 226, 255, 315 levodropropizine 248 lorazepam 473 levofloxacin 519 lorcainide 113, 257 levomepromazine 305 lorcaserin 272 levomethorphan 331 lormetazepam 472 levonorgestrel 483, 484 lornoxicam 460 levoprotiline 306 losartan 543–545 levorphanol 331 losoxantrone 496 levosimendan 411 lotrafiban 361 levovirin 429 lovastatin (mevinolin) 548, 549 librium 466 loxapine 19, 318 licofelone 504 loxiglumide 355 lidocaine 215, 341, 342, 343 loxoprofen 498 295 lidoflazine 241, 345 LSD 246 327 Lieb, Charles 538 lubeluzole , 539 Liebreich, Oscar 188 lubiprostone lignocaine 343 lucanthone 496 233 linagliptin 41, 111, 342, 443 lumefantrine 506 lincomycin 78 lumiracoxib 249 lindane 56 lurasidone 424 linezolid 176 lurtotecan linifanib 371 lusitropics 487 266 linopirdine 403 LY-517717 494 lipase inhibitors 152 lymecycline 295 lipid peroxidation inhibitors 490 lysergic acid diethylamide lipid-lowering drugs, see antilipemics 5-lipoxygenase inhibitors 194 m lirimilast 195 mabuterol 286 lisinopril 336 macitentan 408 Lister, Joseph 82 macrocyclic compounds 557–565 lisuride 192, 295 macrolides 557–564 litracene 306 Maillard reaction 394 liver 13–19 malaria, see antiprotozoals lixivaptan 376 manidipine 449 lobeline 263 mannitol 71, 77 lobucavir 438 MAO inhibitors 117, 216, 259, 270, 271, 273, local anesthetics 77, 84, 215, 216, 224, 236, 293, 400, 401 341–344, 483 MAP kinase inhibitors 366 locomotor stimulants 516 maprotiline 306 lofepramine 114, 311 maraviroc 240 lofexidine 120, 126, 342 marijuana, see THC lomefloxacin 518 marimastat 353 lometrexol 552 masitinib 368 590 Index

matrix metalloproteinase inhibitors 21, 26, mercaptovaline 99, 159, 339 352, 353, 495 Merck & Co. 544 maxipost 200 mercumatilin 451 mazindol 125 mercurous chloride 451 MDMA 275 mercury-containing drugs 451 mebendazole 385 meropenem 525 mechlorethamine 52, 55 mersalyl 451 meclizine 252 mesalazine 511 meclofenamic acid 506 mescaline 145, 275 meclozine 252 mesna 99, 203, 205 medazepam 471 mesotrione 142 medifoxamine 138, 259 mestranol 485 483 medrogestone mesylates 206 285 medroxalol metabolic activation 17–19, 133 482 medroxyprogesterone metaclazepam 472 482 medroxyprogesterone acetate metaldehyde 94 506 mefenamic acid 136, metamizol 181 422 meﬂoquine 111, 414, metapramine 317 454 mefruside metaproterenol 284 482 megestrol acetate metapyrilene 225, 227 77 meglumine metaraminol 282 MEK inhibitors 372 metastat 495 melagatran 362 metaxalone 177 melanin-concentrating hormone receptor-1 metformin 124, 131 antagonists 29 methacycline 494 melatonin 292 methadone 139, 237 melatonin MT /MT agonists 275 1 2 methamphetamine 270 melitracene 306 methanesulfonic esters 206 melogliptin 346 methaqualone 419 meloxicam 460 methazolamide 457 melperone 242 methdilazine 304 melphalan 56, 151 methemoglobin 133 memantine 37, 115 528 menogaril 493 methicillin 182 379 menopausal hot ﬂushes 218 methimazole 99, , 159 menthol 74 methionine meobentine 128 methitural 102 304 meperidine 251 methixene 190 mephentermine 271 methocarbamol 198 mephobarbital 41, 197 methohexital 41, 551 mepindolol 324 methotrexate 147, 305 mepivacaine 343 methotrimeprazine meprobamate 189 methoxsalen 142 meptazinol 274 methoxynaphthylacetic acid 141 mepyramine 227 8-methoxypsoralen 142 mequitazine 304 7-methoxytacrine 420 merbaphen 451 methsuximide 178 mercamphamide 451 4-(methylamino)antipyrine 203 mercaptans 98 methylaminorex 280 mercaptoethanesulfonic acid (mesna) 99, methylanilines 341 203, 205 L-N-methylarginine 129, 157 mercaptoimidazole (thiamazole) 182, 379 methyl benzoate 59 mercaptomerin 451 methyldopa 159 mercaptopurine 99, 439 methylene blue 62 Index 591

3,4-methylenedioxymethamphetamine misonidazole 383 275 misoprostol 538, 541 methylergometrine 295 mitiglinide 150 methylergonovine 295 mitomycin C 300 (R)-α-methylhistamine 379 mitotane 56 methylnaltrexone 334 mitoxantrone 496 methylphenidate 251 mivacurium 289 methylprednisolone 478 mizolastine 258 N-methylpyridinium 397 mizoribine 428 3-methyl-2-thiohydantoin 182 MK-0974 354 methyprylon 199 MK-473 155 methysergide 295 MKC-1 375 metiamide 101 MMI-270 353 metipranolol 324 moclobemide 216 metoclopramide 217 modaﬁnil 146, 157, 168 metocurine 289 moexipril 338 metolazone 138, 453 mofarotene 262 metopimazine 168, 308 mofebutazone 180 metoprolol 39, 93, 325 mofegiline 43 metopyrone 401 molecular modeling 9, 10 metrifonate 74 molecular weight 13–16 metronidazole 17, 378, 383 molluscicides 94 metyrapone 401 molsidomine 161 mevalonate 548 mometasone 479 mevastatin (compactin) 548 monoamine oxidase (MAO) 267, 268 mevinolin (lovastatin) 548, 549 monomethyl fumarate 149 mexazolam 473 montelukast 422 mexiletine 259, 342 moprolol 322 mezlocillin 527 morclofone 261 MGCD-0103 367 mordant yellow 512 mianserin 317, 394 moricizine 17, 307 mibefradil 279 morocromen 192, 278 micafungin 359 morphine 269, 329, 332 Michael acceptors 19, 155 morpholine, pKa 110 miconazole 17, 387, 388 mosapramine 240, 314 microtubule-stabilizing agents 564 mosapride 218 midazolam 471 motesanib 366 midodrine 167, 285, 286 motility, gastrointestinal, see Mietzsch, Fritz 62, 450 gastroprokinetics mifentidine 380 motion sickness 222, 226 mifepristone 490 moxalactam 533 miglitol 72, 77 moxiﬂoxacin 519 miglustat 78 moxonidine 123, 127 migraine 291 MS-275 366 migraine prophylaxis 255 mucolytics 98, 116, 162 milnacipran 237 multidrug resistance gene 16 milrinone 406 multiple sclerosis 169, 398, 461 minaprine 406 muraglitazar 152, 188 mineralocorticoids, see corticosteroids, muscarinic acetylcholine M1 antagonists steroids 313 minocycline 495 muscarinic acetylcholine M3 antagonists minoxidil 70, 407 238 miotics (contract pupil) 190, 380 muscarinic agonists 264 mirtazapine 317, 394 muscarinic antagonists 118, 222, 237 592 Index

muscle relaxants nedocromil 509, 515 – skeletal 75, 115, 126, 160, 177, 183, 189, nefazodone 17, 247 190, 200, 234, 242, 259, 264, 300, 311, nefiracetam 174, 344 410, 419, 468 nefopam 235 – smooth, see anticholinergics, negamycin 161, 355 bronchodilators, vasodilators nelarabine 438 muscular dystrophy 508 nelfinavir 351 mushroom poisons 347 nematodes, see anthelmintics mustards 52, 54–56 nemonapride 219 muzolimine 131, 181, 379 nemonoxacin 519 504 myalex neopentylamine, pKa 110 mycophenolic acid 153 neoplastic diseases, see antineoplastics mydriatics (enlarge pupil) 282, 299 neostigmine 118, 187, 190 myoson 232 nepafenac 168, 500 neramexane 111, 115 373 n neratinib 81 nabilone 86 netilmicin nabumetone 139, 141 netobimin 61, 385 nadolol 323 neuraminidase inibitors 122, 129, 160 nafamostat 127, 164 neuritis 189 nafarelin 358 neurokinin NK1 antagonists 265, 266 nafcillin 48, 526 neurokinin NK3 antagonists 418 nafronyl 48, 221 neuroleptics, see antipsychotics naftazone 182, 192 neuromuscular blocking agents 118, 119, naftidrofuryl 221 289, 290, 300, 490, 491 naftopidil 248, 327 neuroprotectants 95, 211, 246, 249, 259, 283, nalbuphine 333 385 317 nalidixic acid 514, 516 nevirapine 17, 277 nalmefene 333 nexopamil κ naloxone 333 NF- B activation inhibitors 149 naltrexone 333 NHE-1 130 naphazoline 48 niacin 398, 505, 548 naphthalene 47 niaprazine 248 2-naphthylamine 133 nicainoprol 323 naphthyl groups 48 nicardipine 449 1-naphthyl N-methylcarbamate 48 niclosamide 86 1-naphthylthiourea 48 nicorandil 66, 401 naphthyridines 415, 416 nicotinamide 398, 399 naproxen 499 nicotine 393, 402 napsagatran 363 nicotine addiction 272 naratriptan 258, 293 nicotinic acetylcholine agonists 118, 259, narcotic antagonists 119, 239, 330, 331, 333 401 narcotics, see analgesics nicotinic acid 398 naronapride 220 nicotinic agonists 118, 272 nasal decongestants 124, 126, 280, 282 nicotinic receptors 118 nasal dosing, peptides 347 N-nicotinoyl glycine 398 nateglinide 38, 163 nicoumalone 143 National Cancer Institute 415, 554 nifedipine 60, 447 natriuresis enhancers 442 nifekalant 435 nausea, see antiemetics, emetics niflumic acid 394, 507 naveglitazar 151 nifurtimox 183 navitoclax 365 nikethamide 399 nebicapone 85 nilotinib 368 nebivolol 327 nilutamide 60, 179 Index 593 nilvadipine 447 – other pyridines 403, 420 nimesulide 455 – quinones 141 nimetazepam 468 – tryptamine derivatives 297, 298 nimodipine 447 noradrenaline 267 nimorazole 383 noradrenaline reuptake inhibitors 228, 270, nimustine 69 276 nipradilol 323 noradrenaline/dopamine reuptake inhibitors niridazole 183 229 nisoldipine 447 norbutriptyline 313 nitazoxanide 183 norchlorcyclizine 252 nitisinone 142 norcyclizine 252 nitrates 66 nordazepam 60, 169, 394, 467, 469, 472 nitrazepam 60, 468 norepinephrine reuptake inhibitors 228, nitrendipine 60, 447 270, 276 nitric oxide 66 norethindrone 484 nitric oxide synthase inhibitors 128, 129, 157 norethisterone 484 nitriles 184 norfenefrine 281 nitrites 66 norfloxacin 514, 517 nitro compounds 59 norgestimate 483 nitroarenes 59 normeperidine 168 nitrobenzene 59 nornicotine 402 nitrofurans 61, 183 norpropoxyphene 229 nitrofurantoin 60, 183 nortilidine 330 nitrofurazone 183 nortriptyline 312 nitrogen mustards 52, 54–56 norzimeldine 231 nitroglycerin 66, 76 noscapine 269, 288 nitroimidazoles 378 NSAIDs nitroso compounds 68 – arylacetic acids 497–506 nitrosoarenes 60, 135 – arylpropionic acids 303, 497–503 nitrosoureas 54, 68 – benzoic acids 497, 498, 506, 507 nitrothiazoles 183 – other 75, 150, 224, 236, 403, 419, 455, 456 nitrous oxide 161 –phenols85 nizatidine 132 – pyrazolones 180, 181 NK, see neurokinin – salicylates 497, 498, 511–513 NK-611 90 – thiazinecarboxamides 459, 460 142 NMDA antagonists 115, 211, 270, 281, 283, NTBC 427, 501 nucleoside analogs 428–445 noberastine 258 nucleoside phosphorylase inhibitors 439 237 nocloprost 541 nufenoxole 182 nolatrexed 418 NXL-104 , 207 nolomirole 275 nomifensine 136, 230 o nonsedating histamine H1 antagonists obatoclax 375 256–258 obesity 152, 171; see also anorexics nonsense mutation suppressors 508 obidoxime 399 nonsteroidal antiandrogens 170, 179 ocinaplon 370 nonsteroidal antiinflammatory drugs, see octofene 87 NSAIDs octopamine 282 nootropics octreotide 360 – 3-(aryloxy)propylamines 246, 247, 260, odanacatib 353 280 ofloxacin 514, 518 – benzylamines 190 oglemilast 400 – five-membered lactams 173–175 olanzapine 19, 318 – nicotine analogs 259, 264, 401 olaparib 372, 411 594 Index

olcegepant 354 oxazolam 473 olefins 40–44 oxcarbazepine 316 oligoamides 347, 365 oxedrine 35, 282 oligoarylamines 365 oxidative stress inducers 194 oligosaccharides 78–81 N-oxides 70 olmesartan medoxomil 186, 545 oximes 138 olopatadine 145, 312 oxiracetam 72, 175 olpadronic acid 211 oxiranes 96 olsalazine 62, 512 oxisuran 105, 403 omapatrilate 99, 339 oxitriptan 159, 292 omecamtiv mecarbil 372 oxitropium 222 omeprazole 10, 17, 104, 396, 409 oxmetidine 382 oncogenes, see carcinogens oxolinic acid 515 oncolytics, see antineoplastics oxprenolol 322 ondansetron 381 oxybate sodium 149 OPC-6535 508 oxybutynin 165, 221, 233 opiate agonists 239, 241, 243, 274, 329–334 oxycodone 333 opiate antagonists 119, 239, 330, 331, 333 oxymetazoline 124 opiates 329–334 oxyphenbutazone 180 opioid analgesics, see analgesics oxypurinol 439 opipramol 311 oxytetracycline 494 opium 269 oxytocics 295 optimization of leads 13, 20 ozagrel 380 oral bioavailability 6, 14 ozolinon 161 orbofiban 362 orciprenaline 83, 284 p orexin antagonists 288 PA-824 384 organomercurials 451 paclitaxel 554, 555 orlistat 152 pafenolol 326 ormeloxifen 262 Paget’s disease 210 ornidazole 51, 383 pain suppression, see analgesics, NSAIDs orotic acid 435 paliperidone 244 orphenadrine 234 palonosetron 219 ortataxel 556 pamidronic acid 211 orthocaine new 215 pancopride 219 oseltamivir 160, 164 pancuronium 490 osmotic agents 94 panipenem 525 osmotic diuretics 76, 77, 193 panobinostat 156, 294 osmotic laxatives 77, 78 pantoprazole 410 ospemifene 263 Papaver somniferum 269 ostarine 170 papaverine 269, 287 osteoporosis 210, 260–263 paracetamol (acetaminophen) 84,92 otamixaban 363 – metabolism 82 overactive bladder 230, 281 paraldehyde 94 oxacillin 528 parallel synthesis 10 oxaliplatin 158 paraquat 397 oxametacine 147, 502 parasitic infections, see anthelmintics, oxamniquine 287 antiprotozoals oxantel 124 parasympathomimetics, see cholinergics oxantrazole 496 parecoxib 456 oxaprozin 144, 150 parenteral dosing (injection) of drugs 15–17 oxatomide 254 paricalcitol 489 oxazepam 169, 467, 472 Parkinson’s disease, see antiparkinsonians oxazidione 142 paromomycin 81 Index 595 paroxetine 10, 17, 251 PGE1 539 PARP inhibitors 300, 372 PGE2 538 pazinaclone 426 PGG2 538 pazopanib 369, 406 P-gp 13, 16 pazufloxacin 519 pharmacokinetics–structure relationship 5 PDE, see phosphodiesterase phases of clinical development 5 pefloxacin 514, 518 phenacemide 195 PEG (poly(ethylene glycol)) 92, 348 phenacetin 85,91 peldesine 439 phenanthrene 47 Pelletier, Pierre Joseph 413 phenazone 4, 173, 181 pemetrexed 553 phenazopyridine 62, 405 pemirolast 515 phencyclidine 37, 116, 264 pemoline 128 phendimetrazine 280 P-glycoprotein (P-gp) 13, 16 phenelzine 137 P-glycoprotein inhibitors 254, 290, 367 phenethicillin 527 L-penbutolol 47, 320, 321 phenethylamines 267–290 penclomedine 402 pheneturide 193, 195 penciclovir 443 phenformin 124, 131 penethamate 527 pheniramine 230 penfluridol 241 phenmetrazine 280 penicillamine 99, 159, 339 phenobarbital 17, 46, 197 penicillin 522 phenol 36, 82, 84 penicillin F 522 phenols 82 penicillin G 522, 527 – prodrugs 84, 164, 186 penicillin V 522, 527 phenothiazine 303 penicillinase inhibitors 182 phenothiazines 301–309 pentachlorophenol 84 phenoxybenzamine 52 pentamidine 120, 127 phenoxymethylpenicillin 522, 527 pentanols, solubility 36 phenprobamate 190 pentazocine 274 phenprocoumon 142 2-pentenylpenicillin 522 phensuximide 178 pentobarbital 41, 198, 202 phentermine 271 pentopril 338 phentolamine 120, 125, 320 pentostatin 438 phenylacetic acid 149 pentoxifylline 441 N-phenylacetylglutamine 149 pentoxyverine 221 phenylbutazone 4, 46, 180 peptic ulcers, see antiulceratives 4-phenylbutyric acid 149 peptidases 166 phenylephrine 282 peptide deformylase inhibitors 356 phenylethylamines 267 peptides 166, 347, 358–360 phenyl groups, unsubstituted 46 peptidomimetics 347–361 phenylketonuria 408 peramivir 129 phenylpiracetam 175 perampanel 404 phenylpropanolamine 280 perazine 306 phenytoin 17, 179, 213 PERC 57 pheochromocytomas 51 pergolide 294 phocomelia 189 perhexiline 230 pholcodine 108, 332 pericyazine 308 pholedrine 273 perindopril 337 phosphates 213 peristaltic stimulants, see gastroprokinetics phosphodiesterase III inhibitors 247, 406 peroxides 97 phosphodiesterase IV inhibitors 170, 195, perphenazine 109, 308 287, 400, 444, 508 perzinfotel 211 phosphodiesterase V inhibitors 299, 442, pethidine 251 443 596 Index

phosphonates 209 pivampicillin 526 phosphonic acids 209 pixantrone 496 phosphoric acid derivatives 213 pizotifen 255, 315 photosensitizers 90, 142, 564, 565 pizotyline 255, 315 phototoxicity 18, 90 plasma clearance 7 phthalimide, pKa 172 plasma half-life 6, 15 physostigmine 190 plasma protein binding 6 phytoestrogens 88 Plasmodium falciparum 413 picoprazole 396 platelet aggregation inhibitors 265, 366, 439, picosulfate 207 539, 540 picotamide 366 platelet glycoprotein IIb/IIIa blockers 265, Pictet–Spengler reaction 269 361, 362 picumast 247 platinum-containing drugs 158 pidotimod 174 PLD-118 160 pilocarpine 378, 380 pleconaril 385 pilsicainide 344 plerixafor 565 pimavanserin 257 plinabulin 381 pimecrolimus 559 polar surface area 14, 16 pimobendan 411 polidocanol 77 pimonidazole 383 poly(ADP-ribose) polymerase inhibitors 386 pimozide 240 polycyclic hydrocarbons 47 pinacidil 400 poly(ethylene glycol) 92, 348 pinaverium 117 polyols 71–81 pinazepam 169, 470 polythiazide 453 pindolol 323 pomalidomide 196 pioglitazone 178 ponalrestat 502 pipamperone 242 pores, hydrophilic 14, 119 pipecurium 118, 491 posaconazole 391 pipecuronium 491 potassium channel blockers 150, 263, 398, pipemidic acid 514, 518 435, 462, 463 piperacillin 527 potassium channel openers 174, 200, 400, piperazine 109, 250 407 piperazines 109, 227–266 potency of drugs 8, 18 piperidine, pKa 110 Poulenc Freres` 215 piperidines 227–266 pozanicline 259 piperoxan 320 PPAR-γ agonists 151, 152, 178, 179 pipotiazine 308 practolol 47, 321, 324 piracetam 173, 174 pradefovir 443 pirazolac 504 pralatrexate 552 pirbuterol 285 pralidoxime 118, 398 pirenzepine 313 pramiconazole 392 piretanide 455, 508 pramipexole 115, 274 pirfenidone 406 pramiracetam 174 piribedil 250 pramiverine 257 piritramide 239 pranlukast 509 piritrexim 408 pranoprofen 501 pirlindole 293 prasugrel 265 pirmagrel 149 pravastatin 549 pirmenol 71, 233 prazepam 93, 169, 469 piroxicam 186, 396, 460 praziquantel 288 piroximone 182, 400 prazosin 415, 425 pirozantrone 496 preclamol 274 pirprofen 499 preclinical development 5 pitavastatin 550 prednisolone 479 Index 597 prednisone 17, 479 propylamine, pKa 110 pregabalin 161 propylbenzene 91 pregnanolone 483 2-propyl-2-pentenoic acid 148 preladenant 245 propylthiouracil 201, 434 premazepam 475 propyphenazone 181 prenalterol 324 proquazone 419 229 273 prenylamine , prostacyclins 538 232 pridinol 71, prostaglandin analogs 538–542 343 prilocaine prostaglandin antagonists 156, 505 prils 335–340 prostaglandin E (PGE ) 539 421 1 1 primaquine 414, prostaglandins 538 primidone 197 prostatic hyperplasia 278, 279, 416 prinomastat 371 proteases 166 probenecid 17, 458, 507 proteasome inhibitors 352 probucol 87 protein binding 6 procainamide 134, 215, 216 protein kinase C inhibitors 375 procaine 215 304 procarbazine 117, 137 prothipendyl , 393 400 procaterol 283 protionamide 303 prochlorperazine 109, 307 protizinic acid procyclidine 71, 233 proton pump inhibitors 104, 370, 396, 409, prodrugs 410 – amides as 114, 167 protozoals, see antiprotozoals – of alcohols 164, 186, 213, 214 protriptyline 312 – of amides 214 proxyphylline 441 – of amines 112–114, 167, 187 PRT 054021 367 – of carboxylic acids 167, 186 prucalopride 134, 220 – of ketones 140 pruliﬂoxacin 114, 520 – of phenols 84, 164, 186 pruritus (itching), see antipruritics – of thiols 213 pseudohypericin 90 progabide 149 psoralens, see 8-methoxypsoralen progesterone 477, 482 psoriasis 489, 509, 551 progesterone receptor modulators 489 PT-523 552 progestins 477 pteridines 415, 416 progestogens 482–488 pulmonary hypertension 124, 369, 370, 458 150 proglumide purine derivatives 435–439, 443–445 131 proguanil pyrantel 124 prokinetic drugs, see gastroprokinetics pyrazinamide 399 prolactin 274 pyrazofurin 429 prolactin inhibitors 294–296 pyrazolone antipyretics 172 promazine 101, 301, 304, 393 pyrexia, see antiinﬂammatories promethazine 4, 301, 303 pyridine 395, 397 prontosil 62, 450 propafenone 325 pyridine N-oxides 70 propantheline 221 pyridines 393–410 399 propargylamine, pK 110 pyridinol carbamate a 399 propentophylline 441 pyridostigmine 227 propericiazine 308 pyrilamine 225, propiomazine 303 pyrimethamine 405 propiram 227, 401 pyrimidine N-oxides 70 propiverine 220 pyrimidines 25, 27, 393 propofol 82, 84 1-(2-pyrimidinyl)piperazine 250 propoxyphene 228 pyritinol 403 propranolol 47, 320, 321, 322 pyronaridine 417 598 Index

q regadenoson 437 quaternary ammonium salts 118 remifentanil 164, 243 quazepam 201, 470 remikiren 349, 357 quercetin 88 remoxipride 218 quetiapine 19, 319 renin 335 quinacrine 420 renin inhibitors 336, 357 quinagolide 208, 274 renzapride 219 quinapril 338 repaglinide 510 quinazoline 416 repartitioning agents 286 quinazoline N-oxides 466 repinotan 249 quinazolines 415 repirinast 510 quinazolones 418, 419 Research Triangle Institute 415 452 quinethazone reserpine 165, 299 421 quinidine 17, 42, resistance, antibiotic 523 421 quinine 4, 172, 413, respiratory stimulants 234, 253, 263, 399 quinoline 416 retigabine 136, 394, 404 quinolines 24, 412–425 retinoic acid agonists 152, 153, 509 quinolonecarboxylic acids 4, 514–521 retinoic acid metabolism blocking agents 314 quinupramine 111, 391 563 quinupristin revaprazan 370, 406 reverse transcriptase inhibitors 294, 317 r rhein 89 R406 366 rheumatoid arthritis 98, 158, 159, 169, 352, R-115777 380 366 R-115866 391 rhizoxin 564 R-126638 392 Rhone-Poulenc 301 R-406 366 ribavirin 429 rabeprazole 409 ribostamycin 80 raclopride 218 ridogrel 149 radioactive tracing agents 53 rifabutin 562 radiosensitizers 383, 564, 565 rifampin 17, 563 ragaglitazar 152 rifapentine 17 raloxifene 260 rifaximin 563 raltegravir 369 rilmazafone 167 raltitrexed 553 rilmenidine 125 ramatroban 156, 293 rilpivirine 405 rambazole 391 riluzole 385 ramelteon 275 rimantadine 37, 115 ramipril 337 rimiterol 284 ramosetron 381 rimonabant 234 ranitidine 102, 132 riociguat 370, 407 ranolazine 327, 345 risedronic acid 212 rapacuronium 490 risperidone 244 rapamycin 557, 558 ritalinic acid 251 rasagiline 113, 271 ritanserin 256 rate of elimination 7 ritipenem 525 ravuconazole 389 ritodrine 282 razaxaban 370 ritonavir 17, 351 reactive compounds, toxicity 17 rivaroxaban 176 rebamipide 163 rivastigmine 188, 190, 273 reboxetine 228, 322 rivoglitazone 179 recainam 345 rizatriptan 292 5α-reductase inhibitors 487 RNA polymerase inhibitors 562 reﬂux esophagitis, see antiulceratives Ro 03-8799 383 Index 599

Ro 31-1118 325 saralasin 335, 543 Ro 31-7453 375 sarizotan 401 Ro 48-6791 471 sartans 543–547 Ro 48-8684 471 satavaptan 262 rocuronium 491 satraplatin 158 rodenticides 48, 299 saxagliptin 345 rofecoxib 456 Saxl, Paul 451 roflumilast 170, 396, 400 Schering 215 rolapitant 111, 265 schizophrenia 418 rolipram 175, 275 Schmiedeberg, Oswald 188 rolitetracycline 494 scopolamine 96, 222 romidepsin 360 secnidazole 60, 73, 383 ropinirole 275 secobarbital 41, 198 ropivacaine 344 γ-secretase inhibitors 353, 355 roquinimex 461 sedatives, see hypnotics roscovitine 444 seizures, see antiepileptics rosiglitazone 178 P-selectin inhibitors 24 rosoxacin 515 selegiline 271 Ross, Warren 415 seletracetam 43, 175 rosuvastatin 550 selodenoson 438 rotigotine 274 selumetinib 372 roxatidine 264 semagacestat 355 roxifiban 120, 188, 362 sematilide 217 560 roxithromycin senicapoc 151 555 RPR 109881A seratrodast 150 154 RSR-13 sergliflozin etabonate 186 423 rubitecan serine protease inhibitors 127 375 ruboxistaurin serotonin 292 390 rufinamide serotonin antagonists 244, 245, 255, 296 rufloxacin 102, 518 serotonin 5-HT1 agonists 219, 248 rule of five 13 serotonin 5-HT1,2C agonists 250 Runge, Friedlieb 82 serotonin 5-HT agonists 23, 219, 245, 248, 255 316 1A rupatadine 114, , 249 serotonin 5-HT1A antagonists 245, 257 s serotonin 5-HT1A,B,D,F agonists 258 S-8307 543, 544 serotonin 5-HT1B,1D agonists 291–293 S-8308 544 serotonin 5-HT2 antagonists 240, 256, 277 sabeluzole 246, 327 serotonin 5-HT2A agonists 275 safinamide 117, 207 serotonin 5-HT2A antagonists 236, 250 safrole 42 serotonin 5-HT2A,2C agonists 295 sagopilone 564 serotonin 5-HT2A,2C antagonists 234 salbutamol 72, 284 serotonin 5-HT2C agonists 272 salicin 497 serotonin 5-HT3 antagonists 219, 223, 381 salicylamide 168, 512 serotonin 5-HT4 agonists 130, 218–220 salicylamide O-acetic acid 512 serotonin receptors 225 salicylates 497, 498, 511–513 serotonin reuptake inhibitors 228, 234, 236, salicylic acid 497, 498, 511 237, 248, 259, 270, 276 salmeterol 285 serotonin transporter inhibitors 228 salsolinol 287 sertaconazole 388 salt formation, advantages 107 sertindole 246 sapacitabine 432 sertraline 17, 230 sapropterin 408 Sheehan, John C. 522 saquinavir 351 sibrafiban 121, 362 saracatinib 374 sibutramine 112, 272 600 Index

sickle cell disease 151, 509 St. John’s wort 16, 90 side-effects 16–20 stomach 14 silanes 264, 509 Streptomyces 492 sildenafil 442 streptomycin 122, 129 silodosin 279 streptozotocin 69 silperisone 264 strychnine 299 simendan 411 succinimides 177, 178 simvastatin 549 sucralose 51, 79 sirolimus 558 sudoxicam 460 sitafloxacin 520 sufentanyl 243 sitagliptin 23, 273, 346 sulbactam 524 sitaxentan 458 sulbenicillin 204, 528 skin rashes 18 sulfadiazine 458 sleep disorders, see hypnotics sulfadoxine 134, 459 small molecule drugs, future 9 sulfamethoxazole 17, 459 SmithKline Beecham 415 sulfamic acids 207 SMO antagonists 366 sulfamidochrysoidine 62 smoke 17 sulfamoxole 459 SN-38 424 sulfanilamide 62 258 SNS-032 sulfapyridine 459, 512 sodium channel blockers 130, 216, 217, 220, sulfasalazine 62, 512 224, 405, 408 sulfates 207 sodium/proton exchange inhibitors (NHE-1) sulfinpyrazone 180 130, 131 sulfisoxazole 459 solabegron 281 sulfluramid 457 solifenacin 230 sulfonal 193 solubility sulfonamides 21, 450, 452–460; see also – alkanols 36 sulfonylureas – drugs 5, 10, 13, 14 sulfonates 206 –ethers91 sulfones 26, 101, 106 somatostatin analogs 360 sulfonic acids 203–205 sorafenib 371, 396 sulfonic esters 206 sorbinil 178 sorbitol 71, 77 sulfonylureas 462–465 sorivudine 434 sulfoxides 101, 104, 396, 397 87 sotalol 83, 268, 286 sulfoxone sparfloxacin 144, 520 sulfur mustard 54 503 spectinomycin 79 sulindac 105, 156 spermicides 77 sulotroban 217 spiramycin 562 sulpiride 541 spirapril 337 sulprostone 147, 457 spironolactone 487 sulthiame splenda (sucralose) 51, 79 sultopride 218 squalene 548 sultosilic acid 205, 206, 513 SR 121463 262 sumatriptan 291, 292 SR-4554 384 sunitinib 113, 217 stains, see dyes suprofen 500 statins 548–550 surface, see topical stavudine 433 surgery, antiseptic 82 Sternbach, Leo 466 suriclone 426 steroids 477–491 sweeteners, artificial 77, 79, 115, 205, 434 stibogluconate 158 sympathomimetics, see adrenergic agonists stimulants, see CNS stimulants synephrine 267, 282 stiripentol 74 syphilis 451 Index 601 t temocillin 529 T4, thyroxine 159 temoporfin 564 tabimorelin 356 temozolomide 65, 382 TAC-101 509 temsirolimus 558 tachyarrhythmias, see antiarrhythmics tenatoprazole 409 tacrine 414, 420 tenidap 139, 459 tacrolimus 557, 559 teniposide 90 tadalafil 299 tenofovir disoproxil 210, 444 tafenoquine 421 tenoxicam 459 TAK-375 275 tepa 55 TAK-442 170 tepoxalin 504 Takeda 543 teprenone 141 talabostat 355 teprotide 335 talampanel 476 teratogenics 189 talampicillin 526 terazosin 426 talbutal 198 terbinafine 48, 116, 271 talinolol 325 terbogrel 149 talnetant 418 terbutaline 3, 284 talsaclidine 44, 264 terfenadine 226, 256 taltobulin 356 terguride 294 tamibarotene 509 teriflunomide 169 tamoxifen 263 terodiline 229 tamsulosin 279 tert-alkylamine dealkylation 111 tandospirone 249 tertatolol 320, 323 tanomastat 505 tertiary alcohols 71, 73 tapentadol 274 terutroban 162 taranabant 171, 396 tesaglitazar 152, 206 tariquidar 367 tesofensine 111, 112, 251 TAS-106 431 testosterone 477, 486 tasosartan 546, 547 tetomilast 508 tauromustine 69 tetrabenazine 287 taxanes 554–556 tetrachlorodioxin 52 taxol 10, 554, 555 tetrachloroethylene 57 tazarotene 509 tetracycline 493 tazifylline 442 tetracyclines 492–495 tazobactam 524 tetrahydrocannabinol (THC) 86, 146 TBC-3711 369 tetrahydrofolic acid 552 TBR-652 382 tetrahydrofuran 91, 100 tebufelone 85 tetrahydroisoquinolines 269, 287–290 tecadenoson 438 tetrahydropyran 100 tecans 415, 423, 424 tetrahydrothiophene 100 tecarfarin 143 tetrazepam 468 tedisamil 263 tetrazoles 146 tegafur 434 tezosentan 509 tegaserod 122, 130 thalidomide 172, 189, 195 telaprevir 351 thalline 4, 173 telbivudine 433 tham 115 telcagepant 192, 354 THC 86, 146 telithromycin 561 thebaine 269 telmisartan 546 theobromine 440, 451 temafloxacin 517 theophylline 440 temazepam 138, 472 therapeutic index 5 temelastine 402 THF 91, 100 temocapril 102, 338 thiabendazole 378, 386 602 Index

thiamazole 182, 379 tirilazad 490 thiamphenicol 78 tirofiban 361 thiazinamium 303 tiropramide 261 thiazolidinediones 178, 179 tizanidine 123, 126 thiethylperazine 307 tizoxanide 183 thioacetamide 201 TMC-207 417 thioamides 194 tobacco alkaloids 402 thiocarbonyl compounds 201 tobramycin 80 thioethers 100 tocainide 343 thioguanine 201, 439 tocolytics (inhibitors of uterine motility) thiols 98 282, 283, 286 – prodrugs 213, 214 D-α-tocopherol 86 thionylan 227 tofisopam 476 thiopental 199, 202 tolamolol 327 thiophene S-oxides 102, 103 tolazamide 463 thioridazine 17, 306 tolazoline 124, 320 thiotepa 55 tolbutamide 52, 462 thiothixene 307 tolcapone 85 thioureas 194 tolfenamic acid 506 thrombin inhibitors 349, 354, 363, 364; see tolmetin 503 also antithrombotics toloxatone 176 thrombolytic drugs, see antithrombotics tolperisone 242 thromboxane antagonists 149, 150, 156, 542 tolrestat 163 thromboxane synthase inhibitors 149, 380, tolterodine 232 510 toluene 47 thromboxanes 538 o-toluidine 133, 341, 343 thymidylate synthase inhibitors 418 tolvaptan 376 thyroxine, T4 159 tomopenem 525 tiagabine 161, 240 tomudex 553 tiamenidine 127 topical anesthetics, see local anesthetics tianeptine 146, 313 topical antifungals, see antifungals tiapride 217 topical disinfectants 82, 87, 118 tiaprofenic acid 503 topiramate 95, 207 tiaramide 224 topixantrone 496 tiazofurin 429 topoisomerase I inhibitors 299, 415, 423, tibolone 484 424 ticagrelor 439 topoisomerase II inhibitors 416, 496 ticarcillin 529 topotecan 415, 424 ticlopidine 17, 265 torasemide 463 ticrynafen 102, 103, 155 torcetrapib 191 tienilic acid 155 toremifene 263 tigecycline 495 torsades de pointes 17 tilidine 43, 330 torsemide 463 tiludronic acid 212 tosedostat 156, 353 timolol 326 tosufloxacin 516 timoprazole 396 toxicity of drugs 17 tinidazole 106, 382 TPA-023 391 tinofedrine 232 trabectedin 288 tiopronin 99, 162, 339 tramadol 330 tiotropium 96, 222 tramiprosate 204 tipifarnib 380 trandolapril 337 tipranavir 143 tranexamic acid 160 tiracizine 187, 313 tranezamic acid 160 tirapazamine 70, 419 tranilast 507 Index 603 tranquilizers, see antipsychotics, hypnotics tropane alkaloids 222–224 transplant rejection 557 tropisetron 223 tranylcypromine 270 trospectomycin 79 trapidil 440 trovafloxacin 167, 516 travoprost 147, 540 troxacitabine 138, 430 traxoprodil 283 tryptamine 107 trazodone 247 tuberculostatics 201, 399, 400, 417; see also trefentanil 243 antibacterials tremor, see antidyskinetics, antiparkinsonians D-tubocurarine 289 treprostinil 540 tubular secretion 15 tretinoin (all-trans-retinoic acid, vitamin A tubulin ligands 291 acid) 153 tubulin polymerization inhibitors 356, 381 triamcinolone 478 tucaresol 138, 509 triamcinolone acetonide 479 tulobuterol 281 1,2,4-triaminobenzene 62 TXA2 538 triamterene 408 tybamate 189 triazenes 64 tyramine 107, 267 triazolam 470 tyrosine kinase inhibitors, see antineoplastics triazoles 387–392 tyrosinemia 142 trichlormethiazide 453 trichloroacetaldehyde 138 u trichloroacetic acid 138, 148 U-101387 246 1,2,4-trichlorobenzene 56 UCB 173 trichloroethanol 74, 138 udenafil 443 triclabendazole 385 UK-240455 427 triclopyr 155, 402 ulcers, gastric tricyclic antidepressants, see antidepressants – drugs for treatment, see antiulceratives triethylamine, pK 110 a – NSAID-associated 497, 498 trifluoperazine 307 ulifloxacin 114, 520 trifluoroacetamides 166 ulipristal acetate 136, 490 trifluoromethyl groups 51 undesirable effects of drugs (adverse drug trifluorothymidine 433 reactions) 17–20 triflupromazine 305 unoprostone isopropyl 541 trifluridine 433 unsaturated groups (alkenes) 40–44 triflusal 511, 512 UR-8880 455 trigonelline 398 uracilacetic acid 53, 433 trihexyphenidyl 233 urapidil 248, 435 triiodobenzoic acid 75 urea cycle disorders 149 trimazosin 73, 426 urea 193 trimebutine 220 ureas 28, 29, 192–199 trimecaine 343 ureides 146 trimeprazine 305 urethanes (carbamates) 187–191 trimetazidine 252 uricosurics (enhancers of uric acid excretion) trimethadione 177 88, 155, 180, 435, 458 trimethobenzamide 260 urinary acidifiers 116, 159 trimethoprim 404 urinary incontinence 220, 232, 238 trimetrexate 136, 409 urogenital atrophy 263 trimipramine 314 tripamide 453 tripelennamine 225, 227 v triprolidine 145, 231 V-11294A 444 trocade 352 vadimezan 505 troglitazone 17, 179 valacyclovir 437 trombopoetin agonists 153 valdecoxib 456 604 Index

valium 468 vindesine 298 valnoctamide 148 vinflunine 298 valproic acid 144, 148 vinorelbine 297 N-valproylglycine 162 vinpocetine 298 valrocemide 162 vinyl bromides 53 valsartan 547 vinyl chloride 49 vamicamide 238 vinyl chlorides 52 vancomycin 361 vinyl fluorides 43 vandetanib 373 vinyl groups 40–43 vanilloid-1 antagonists 25 vinylbital 199 vanoxerine 241 viral infections, see antivirals vapiprost 542 viramidine 429 vardenafil 443 vismodegib 366 varenicline 272, 422 vitamin A 153 398 399 vascular disrupting agents 381 vitamin B3 , vasoconstrictors 126, 296, 505 vitamin B9 551 vasodilators vitamin C 77 – cerebral 221, 236, 283, 287, 298, 422, 440 vitamin D analogs 488, 489 488 – coronary 66, 93, 94, 229, 230, 241, 278, 440 vitamin D2 489 – peripheral 236, 242, 250, 282, 283, 285, vitamin D3 401, 437, 441, 539, 540 vitamin E (tocopherol) 86 162 vasopressin agonists 360 vitamin H (biotin) vasopressin antagonists 262, 376 vitamin K antagonists 143 vasopressors (antihypotensives) Vogl, Alfred 451 273, 282, 285, 407 volume of distribution 6 vasoprotectants 88, 182 volume, body fluids 7 vatalanib 372, 421 vomiting, see antiemetics, emetics Vater, Wulf 446 von Mering, Josef 188, 193 516 vecuronium 490 voreloxin 389 vegetables 17 voriconazole 156 VEGF inhibitors 371, 373 vorinostat 366 veliparib 386 VX-702 velnacrine 414, 420 vemurafenib 370 w venlafaxine 276 Wani, Mansukh C. 554 veralipride 218 warfarin 60, 139, 142, 349 verapamil 17, 277, 446 weight reduction, see anorexics verlukast 423 Western yew tree 554 vernakalant 330 willow bark extracts 497 veronal 193 Willstatter,¨ Richard 215 verteporfin 565 Wintersteiner, Oskar 522 vertigo 401; see also motion sickness Wong, Pancras C. 543 vesnarinone 425 worms, see anthelmintics vicriviroc 253 vidarabine 436 x vigabatrin 43, 161 xamoterol 327 vilazodone 248 xanomeline 264 vildagliptin 342, 346 xanthine oxidase inhibitors 439, 445, viloxazine 280, 322 510 vinblastine 297 xemilofiban 363 vinca alkaloids 291, 297, 298 xibenolol 321 vincamine 298 ximelagatran 121, 362 vincristine 297 ximoprofen 499 Index 605 xipamide 454 zenarestat 502 X-ray contrast agents 72, 75, 76 zidovudine 58, 432 zileuton 192, 194 231 y zimeldine 71, ziprasidone 244 YH1885 370, 406 zofenopril 164, 339 YM-150 367 zoledronic acid 212 yohimbine 299 zolmitriptan 292 zolpidem 52, 410 z zomepirac 503 zafirlukast 511 zonampanel 501 zalcitabine 430 zoniporide 131 zaleplon 371 zonisamide 457 zaltoprofen 501 zopiclone 427 zamifenacin 278 zopolrestat 502 zanamivir 122, 129 zosuquidar 254, 327 zatebradine 277 zotarolimus 558 zatosetron 223 zotepine 140, 318 ZD 9331 147, 552 zuclopenthixol 308 zebularine 429