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 2012 2011 ISBN: 978-3-527-32954-0 ISBN: 978-0-470-68446-7 Gad, S. C. (ed.) Rankovic, Z., Morphy, R. Development of Therapeutic Lead Generation Approaches Agents Handbook in Drug Discovery 2012 2010 ISBN: 978-0-471-21385-7 ISBN: 978-0-470-25761-6 Tsaioun, K., Kates, S. A. (eds.) Han, C., Davis, C. B., Wang, B. (eds.) ADMET for Medicinal Chemists Evaluation of Drug Candidates A Practical Guide for Preclinical Development 2011 Pharmacokinetics, Metabolism, ISBN: 978-0-470-48407-4 Pharmaceutics, and Toxicology 2010 ISBN: 978-0-470-04491-9 Sotriffer, C. (ed.) Virtual Screening Principles, Challenges, and Practical Faller, B., Urban, L. (eds.) Guidelines Hit and Lead Profiling 2011 Identification and Optimization ISBN: 978-3-527-32636-5 of Drug-like Molecules 2009 ISBN: 978-3-527-32331-9 Florencio Zaragoza Dorwald¨ Lead Optimization for Medicinal Chemists Pharmacokinetic Properties of Functional Groups and Organic Compounds The Author All books published by Wiley-VCH are carefully produced. Nevertheless, authors, Dr. Florencio Zaragoza D¨orwald editors, and publisher do not warrant the Lonza AG information contained in these books, Rottenstrasse 6 including this book, to be free of errors. 3930 Visp Readers are advised to keep in mind that Switzerland statements, data, illustrations, procedural details or other items may inadvertently be Cover illustration: inaccurate. Mobile in the style of Alexander Calder. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>. 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Cover Adam-Design, Weinheim Typesetting: Laserwords Private Limited, Chennai, India Printing and Binding: Strauss GmbH, Morlenbach,¨ Germany Printed on acid-free paper Print ISBN: 978-3-527-33226-7 ePDF ISBN: 978-3-527-64566-4 oBook ISBN: 978-3-527-64564-0 ePub ISBN: 978-3-527-64565-7 Mobi ISBN: 978-3-527-64567-1 V 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.