An Introduction to Medicinal

Chemistry FIFTH EDITION

Graham L. Patrick

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Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Graham L. Patrick 2013 Th e moral rights of the author have been asserted Second Edition copyright 2001 Th ird Edition copyright 2005 Fourth Edition copyright 2009 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer British Library Cataloguing in Publication Data Data available ISBN 978–0–19–969739–7 Printed in Italy by L.E.G.O. S.p.A.—Lavis TN Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Patrick97397.indb iv 11/28/2012 9:11:46 PM Preface

Th is text is aimed at undergraduates and postgradu- tors, enzymes, and nucleic acids. Students with a ates who have a basic grounding in chemistry and are strong background in biochemistry will already know studying a module or degree in medicinal chemistry. It this material, but may fi nd these chapters a useful attempts to convey, in a readable and interesting style, revision of the essential points. an understanding about drug design and the molecular • Part B covers pharmacodynamics in Chapters 7–10 mechanisms by which drugs act in the body. In so doing, and pharmacokinetics in Chapter 11. Pharmacody- it highlights the importance of medicinal chemistry in all namics is the study of how drugs interact with their our lives and the fascination of working in a fi eld which molecular targets and the consequences of those overlaps the disciplines of chemistry, biochemistry, interactions. Pharmacokinetics relates to the issues physiology, microbiology, cell biology, and pharmacol- involved in a drug reaching its target in the fi rst place. ogy. Consequently, the book is of particular interest to • Part C covers the general principles and strategies students who might be considering a future career in the involved in discovering and designing new drugs and pharmaceutical industry. developing them for the marketplace. • Part D looks at particular ‘tools of the trade’ which are invaluable in drug design, i.e. QSAR, combinatorial New to this edition synthesis, and computer-aided design. • Part E covers a selection of specifi c topics within Following the success of the fi rst four editions, as well medicinal chemistry—antibacterial, antiviral and as useful feedback from readers, there has been some anticancer agents, cholinergics and anticholinest- reo rganization and updating of chapters, especially those erases, adrenergics, opioid analgesics, and anti- in Part E. ulcer agents. To some extent, those chapters refl ect Chapters have been modifi ed, as appropriate, to refl ect the changing emphasis in medicinal chemistry contemporary topics and teaching methods. Th is includes: research. Antibacterial agents, cholinergics, adrenergics, and opioids have long histories and much of • new coverage of 99 drugs not featured in the previous the early development of these drugs relied heav- edition; ily on random variations of lead compounds on • six new boxes, covering topics such ‘Cyclodextrins as a trial and error basis. Th is approach was waste- drug scavengers’, ‘Th e structure-based drug design of ful but it led to the recognition of various design crizotinib’, and ‘Designing a non-steroidal glucocorti- strategies which could be used in a more rational coid agonist’; approach to drug design. Th e development of the • a new case study on steroidal anti-infl ammatory agents; anti-ulcer drug cimetidine (Chapter 25) represents • over 25 new sections, providing additional depth in one of the early examples of the rational approach subject areas including ‘Tethers and anchors’ and to medicinal chemistry. However, the real revolu- ‘Short-acting β-blockers’; tion in drug design resulted from giant advances • additional end-of-chapter questions; made in molecular biology and genetics which have • current reference lists. provided a detailed understanding of drug targets We have also made signifi cant changes to the Online and how they function at the molecular level. Th is, Resource Centre, adding 40 molecular modelling exer- allied to the use of molecular modelling and X-ray cises and 16 web articles. crystallography, has revolutionized drug design. Th e development of protease inhibitors as antiviral agents (Chapter 20), kinase inhibitors as anticancer The structure of the book agents (Chapter 21), and the statins as cholesterol- lowering agents (Case study 1) are prime examples Following the introductory chapter, the book is divided of the modern approach. into fi ve parts. • Part A contains six chapters that cover the structure G. L. P. and function of important drug targets, such as recep- November 2012

Patrick97397.indb v 11/28/2012 9:11:46 PM About the book

The fifth edition of An Introduction to Medicinal Chemistry and its accompanying companion web site contains many learning features which will help you to understand this fascinating subject. This section explains how to get the most out of these.

present in the drug can be important in forming inter- one or more of the following interactions, but not neces- Emboldened key words molecular bonds with the target binding site. If they do sarily all of them. so, they are called binding groups. However, the carbon skeleton of the drug also plays an important role in bind- 1.3.1 Electrostatic or ionic bonds ing the drug to its target through van der Waals interac- Terminology is emboldened and defined in a glossary tions. As far as the target binding site is concerned, it too An ionic or electrostatic bond is the strongest of the contains functional groups and carbon skeletons which intermolecular bonds (20–40 kJ mol−1) and takes place at the end of the book, helping you to become familiar can form intermolecular bonds with ‘visiting’ drugs. between groups that have opposite charges, such as The specific regions where this takes place are known as a carboxylate ion and an aminium ion (Fig. 1.5). The binding regions. The study of how drugs interact with strength of the interaction is inversely proportional to with the language of medicinal chemistry. their targets through binding interactions and produce the distance between the two charged atoms and it is a pharmacological effect is known as pharmacodynamics. also dependent on the nature of the environment, being

Boxes BOX 3.1 The external control of enzymes by nitric oxide

The external control of enzymes is usually initiated by called cyclases to generate cyclic GMP from GTP (Fig. 2). Boxes are used to present in-depth material and to external chemical messengers which do not enter the cell. Cyclic GMP then acts as a secondary messenger to inﬂu- However, there is an exception to this. It has been discov- ence other reactions within the cell. By this process, nitric explore how the concepts of medicinal chemistry are ered that cells can generate the gas nitric oxide by the reac- oxide has an inﬂuence on a diverse range of physiological tion sequence shown in Fig. 1, catalysed by the enzyme processes, including blood pressure, neurotransmission, and nitric oxide synthase. immunological defence mechanisms. applied in practice. Because nitric oxide is a gas, it can diffuse easily through cell membranes into target cells. There, it activates enzymes

H2N CO2H H2N CO2H H2N CO2H

their pharmacological effect. KEY POINTS Key points By chemical structure Many drugs which have a com- t %SVHTBDUPONPMFDVMBSUBSHFUTMPDBUFEJOUIFDFMMNFNCSBOF mon skeleton are grouped together, for example penicil- PGDFMMTPSXJUIJOUIFDFMMTUIFNTFMWFT lins, barbiturates, opiates, steroids, and catecholamines. t %SVH UBSHFUT BSF NBDSPNPMFDVMFT UIBU IBWF B CJOEJOH TJUF In some cases, this is a useful classification as the biologi- Summaries at the end of major sections within chapters JOUPXIJDIUIFESVHmUTBOECJOET cal activity and mechanism of action is the same for the structures involved, for example the antibiotic activity t .PTUESVHTCJOEUPUIFJSUBSHFUTCZNFBOTPGJOUFSNPMFDVMBS of penicillins. However, not all compounds with similar highlight and summarize key concepts and provide a CPOET chemical structures have the same biological action. For t 1IBSNBDPEZOBNJDTJTUIFTUVEZPGIPXESVHTJOUFSBDUXJUI example, steroids share a similar tetracyclic structure, but basis for revision. UIFJSUBSHFUTBOEQSPEVDFBQIBSNBDPMPHJDBMFGGFDU they have very different effects in the body. In this text, t &MFDUSPTUBUJDPSJPOJDJOUFSBDUJPOTPDDVSCFUXFFOHSPVQTPG various groups of structurally-related drugs are discussed,

Questions QUESTIONS

1. Enzymes can be used in organic synthesis. For example, estradiol in the presence of the cofactor NADH. The initial End-of-chapter questions allow you to test your the reduction of an aldehyde is carried out using aldehyde rate data for the enzyme-catalysed reaction in the absence dehydrogenase. Unfortunately, this reaction requires the of an inhibitor is as follows: use of the cofactor NADH, which is expensive and is used Substrate concentration (10−2 mol dm−3) 5 10 25 50 100 understanding and apply concepts presented in the up in the reaction. If ethanol is added to the reaction, only chapter. catalytic amounts of cofactor are required. Why? Initial rate (10−1 mol dm−3 s−1) 28.6 51.5 111 141 145 2. Acetylcholine is the substrate for the enzyme Create a Michaelis Menton plot and a Lineweaver-Burk

acetylcholinesterase. Suggest what sort of binding plot. Use both plots to calculate the values of KM and the

Further reading FURTHER READING

Broadwith, P. (2010) Enzymes do the twist. Chemistry World. Navia, M. A. and Murcko, M. A. (1992) Use of structural Selected references allow you to easily research those Available at: http://www.rsc.org/chemistryworld/News/2010/ information in drug design. Current Opinion in Structural January/06011001.asp (last accessed 14 June 2012). Biology 2, 202–216. topics that are of particular interest to you. Knowles, J. R. (1991) Enzyme catalysis: not different, just Teague, S. J. (2003) Implications of protein ﬂexibility for drug better. Science 350, 121–124. discovery. Nature Reviews Drug Discovery 2, 527–541. Maryanoff, B. E. and Maryanoff, C. A. (1992) Some thoughts on enzyme inhibition and the quiescent afﬁnity label concept. Advances in Medicinal Chemistry 1, 235–261.

Appendix Appendix 1 The appendix includes an index of drug names and their Essential amino acids

corresponding trade names, and an extensive glossary. NON POLAR (hydrophobic) H HH HH

H3NCCCO2 H3NCO2 H3NCC CO2 H3NCO2 H3N CCO2

Patrick97397.indb vi 11/28/2012 9:11:46 PM About the Online Resource Centre

Online Resource Centres provide students and lecturers with ready-to-use teaching and learning resources. They are free of charge, designed to complement the textbook, and offer additional materials which are suited to electronic delivery. You will find the material to accompany An Introduction to Medicinal Chemistry at: www.oxfordtextbooks.co.uk/orc/patrick5e/

Student resources Lecturer resources

Rotatable 3D structures For registered adopters of the book Links to where you can view the structures from the book in interactive rotating form. All these resources can be downloaded and are fully customizable, allowing them to be incorporated into Web articles your institution’s existing virtual learning environment. Developments in the field since the book published and further information that you may find of interest. Test bank A bank of multiple choice questions, which can be Molecular modelling exercises downloaded and customized for your teaching. Develop your molecular modelling skills, using Wavefunction’s SpartanTM software to answer the set Answers questions. To answer all the questions, you will need Answers to end-of-chapter questions. the full version of Spartan, which is widely distributed at colleges and universities; check with your institution Figures from the book for access. All of the figures from the textbook are available You will be able to answer a selection of the questions to download electronically for use in lectures and and familiarize yourself with the basics using Spartan handouts. Student EditionTM. Students can purchase this from store.wavefun.com/product_p/SpStudent.htm. Enter PowerPoint slides the promotional code OUPAIMC to receive 20% PowerPoint slides are provided to help teach selected discount for students using An Introduction to Medicinal topics from the book. Chemistry. For questions or support for SpartanTM, visit www.wavefun.com. Multiple choice questions Test yourself on the topics covered in the text and receive instant feedback.

Patrick97397.indb vii 11/28/2012 9:11:49 PM Acknowledgements

Th e author and Oxford University Press would like to Professor John Carran, Department of Chemistry, thank the following people who have given advice on Queen’s University, Canada the various editions of this textbook: Professor Anne Johnson, Department of Chemistry and Biology, Ryerson University, Canada Dr Lee Banting, School of Pharmacy and Biomedical Dr Jane Hanrahan, Faculty of Pharmacy, University of Sciences, University of Portsmouth, UK Sydney, Australia Dr Don Green, Department of Health and Human Dr Ethel Forbes, School of Science, University of West Sciences, London Metropolitan University, UK of Scotland, UK Dr Mike Southern, Department of Chemistry, Trinity Dr Zoë Waller, School of Pharmacy, University of East College, University of Dublin, Ireland Anglia, UK Dr Mikael Elofsson (Assistant Professor), Department Dr Susan Matthews, School of Pharmacy, University of of Chemistry, Umeå University, Sweden East Anglia, UK Dr Ed Moret, Faculty of Pharmaceutical Sciences, Professor Ulf Nilsson, Organic Chemistry, Lund Utrecht University, the Netherlands University, Sweden Professor John Nielsen, Department of Natural Sciences, Dr Russell Pearson, School of Physical and Geographical Royal Veterinary and Agricultural University, Sciences, Keele University, UK Denmark Dr Rachel Codd, Sydney Medical School, Th e University Professor Henk Timmerman, Department of Medicinal of Sydney, Australia Chemistry, Vrije Universiteit, the Netherlands Dr Marcus Durrant, Department of Chemical and Professor Nouri Neamati, School of Pharmacy, University Forensic Sciences, Northumbria University, UK of Southern California, USA Dr Alison Hill, College of Life and Environmental Professor Kristina Luthman, Department of Chemistry, Sciences, University of Exeter, UK Gothenburg University, Sweden Dr Connie Locher, School of Biomedical, Biomolecular Professor Taleb Altel, College of Pharmacy, University of and Chemical Sciences, University of Western Sarjah, United Arab Emirates Australia, Australia Professor Dirk Rijkers, Faculty of Pharmaceutical Dr Angeline Kanagasooriam, School of Physical Sciences, Sciences, Utrecht University, the Netherlands University of Kent, UK Dr Sushama Dandekar, Department of Chemistry, Jon Våbenø, Department of Pharmacy, University of University of North Texas, USA Tromsø, Norway Dr John Spencer, Department of Chemistry, University of Sussex, UK Th e author would like to express his gratitude to Dr Angeline Kanagasooriam, School of Physical Sciences, Dr John Spencer of the University of Sussex for co- University of Kent at Canterbury, UK authoring Chapter 16, the preparation of several web Dr A Ganesan, School of Chemistry, University of articles, and for feedback during the preparation of this Southampton, UK fi ft h edition. Much appreciation is owed to Nahoum Dr Rachel Dickens, Department of Chemistry, University Anthony and Dr Rachel Clark of the Strathclyde Institute of Durham, UK for Pharmaceutical and Biomedical Sciences at the Dr Gerd Wagner, School of Chemical Sciences and University of Strathclyde for their assistance with creating Pharmacy, University of East Anglia, UK Figures 2.9; Box 8.2, Figures 1 and 3; and Figures 17.9, Dr Colin Fishwick, School of Chemistry, University of 17.44, 20.15, 20.22, 20.54, and 20.55 from pdb fi les, some Leeds, UK of which were obtained from the RSCB Protein Data Professor Paul O’Neil, Department of Chemistry, Bank. Dr James Keeler of the Department of Chemistry, University of Liverpool, UK University of Cambridge, kindly generated the molecular Professor Trond Ulven, Department of Chemistry, models that appear on the book’s Online Resource Centre. University of Southern Denmark, Denmark Th anks also to Dr Stephen Bromidge of GlaxoSmithKline Professor Jennifer Powers, Department of Chemistry and for permitting the description of his work on selective Biochemistry, Kennesaw State University, USA 5-HT2C antagonists, and for providing many of the Professor Joanne Kehlbeck, Department of Chemistry, diagrams for that web article. Finally, many thanks to Union College, USA Cambridge Scientifi c, Oxford Molecular, and Tripos for Dr Robert Sinclair, Faculty of Pharmaceutical Sciences, their advice and assistance in the writing of Chapter 17. University of British Columbia, Canada

Patrick97397.indb viii 11/28/2012 9:11:50 PM List of boxes

General interest 17.5 Constructing a receptor map 369 17.6 Designing a non-steroidal glucocorticoid 378 3.1 The external control of enzymes by nitric 38 agonist oxide 18.1 Altering log P to remove central nervous 387 7.1 A cure for antifreeze poisoning 88 system side effects 7.2 Irreversible inhibition for the treatment of 90 18.2 Insecticidal activity of diethyl phenyl 390 obesity phosphates 7.3 Suicide substrates 94 18.3 Hansch equation for a series of 393 7.4 Designing drugs to be isozyme-selective 95 antimalarial compounds 7.5 Action of toxins on enzymes 96 19.1 Sulphonamide analogues with reduced 417 8.1 An unexpected agonist 106 toxicity 8.2 Estradiol and the estrogen receptor 109 19.2 Treatment of intestinal infections 418 19.5 The isoxazolyl penicillins 432 10.1 Antidepressant drugs acting on transport 136 19.7 Ampicillin prodrugs 434 proteins 19.20 Organoarsenicals as antiparasitic drugs 465 10.2 Targeting transcriptor factors: co-activator 140 21.7 Development of a non-peptide farnesyl 547 interactions transferase inhibitor 10.3 Cyclodextrins as drug scavengers 150 21.10 Design of sorafenib 557 11.1 Metabolism of an antiviral agent 164 21.13 Gemtuzumab ozogamicin: an antibody– 571 12.1 Recently discovered targets: the caspases 190 drug conjugate 12.2 Pitfalls in choosing particular targets 192 22.1 Mosses play it smart 604 12.3 Early tests for potential toxicity 193 24.3 Opioids as anti-diarrhoeal agents 644 12.4 Selective optimization of side activities 205 24.6 Design of naltrindole 651 (SOSA) 12.5 Natural ligands as lead compounds 206 Synthesis 12.6 Examples of serendipity 207 15.2 Synthesis of ebalzotan 287 12.7 The use of NMR spectroscopy in fi nding 209 15.3 Synthesis of ICI D7114 287 lead compounds 16.2 Dynamic combinatorial synthesis of vanco- 334 12.8 Click chemistry in situ 211 mycin dimers 13.1 Converting an enzyme substrate to an 232 19.9 Synthesis of 3-methylated cephalosporins 439 inhibitor by extension tactics 19.17 Synthesis of ciprofl oxacin 458 13.2 Simplifi cation 237 21.8 General synthesis of gefi tinib and related 550 13.3 Rigidifi cation tactics in drug design 240 analogues 13.4 The structure-based drug design of 242 21.9 General synthesis of imatinib and 553 crizotinib analogues 14.1 The use of bioisosteres to increase 251 23.2 Synthesis of salbutamol 619 absorption 23.3 Synthesis of aryloxypropanolamines 623 14.2 Shortening the lifetime of a drug 256 24.2 Synthesis of N -alkylated morphine 639 14.3 Varying esters in prodrugs 260 analogues 14.4 Prodrugs masking toxicity and side effects 262 24.4 Synthesis of the orvinols 646 14.5 Prodrugs to improve water solubility 263 25.1 Synthesis of cimetidine 672 15.1 Drug metabolism studies and drug design 276 25.2 Synthesis of omeprazole and 686 16.1 Examples of scaffolds 320 esomeprazole 17.1 Energy minimizing apomorphine 340 CS2.1 Synthesis of captopril and enalaprilate 297 17.2 Study of HOMO and LUMO orbitals 344 CS4.1 Synthesis of oxamniquine 310 17.3 Finding conformations of cyclic structures 347 by molecular dynamics 17.4 Identifi cation of an active conformation 353

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Clinical correlation 20.2 Clinical aspects of antiviral drugs used 478 against HIV 19.3 Clinical properties of benzylpenicillin and 423 20.3 Clinical aspects of reverse transcriptase 481 phenoxymethylpenicillin inhibitors 19.4 Pseudomonas aeruginosa 426 20.4 Clinical aspects of protease inhibitors 493 β 19.6 Clinical aspects of -lactamase-resistant 432 (PIs) penicillins 21.1 Clinical aspects of intercalating agents 525 19.8 Clinical aspects of broad-spectrum 435 21.2 Clinical aspects of non-intercalating 527 penicillins agents inhibiting the action of 19.10 Clinical aspects of cephalosporins 442 topoisomerase enzymes on DNA 19.11 Clinical aspects of miscellaneous 443 21.3 Clinical aspects of alkylating and 530 β -lactam antibiotics metallating agents 19.12 Clinical aspects of cycloserine, 451 21.4 Clinical aspects of antimetabolites 533 bacitracin, and vancomycin 21.5 Clinical aspects of hormone-based 540 19.13 Clinical aspects of drugs acting on the 452 therapies plasma membrane 21.6 Clinical aspects of drugs acting on 543 19.14 Clinical aspects of aminoglycosides 453 structural proteins 19.15 Clinical aspects of tetracyclines and 454 21.11 Clinical aspects of kinase inhibitors 559 chloramphenicol 21.12 Clinical aspects of antibodies and 569 19.16 Clinical aspects of macrolides, 457 antibody–drug conjugates lincosamides, streptogramins, and 23.1 Clinical aspects of adrenergic agents 611 oxazolidinones 23.4 Clinical aspects of β-blockers 624 19.18 Clinical aspects of quinolones and 459 24.1 Clinical aspects of morphine 633 ﬂ uoroquinolones 24.5 A comparison of opioids and their effects 649 19.19 Clinical aspects of rifamycins and 462 on opioid receptors miscellaneous agents CS3.1 Clinical properties of artemisinin and 303 20.1 Clinical aspects of viral DNA polymerase 475 analogues inhibitors CS6.1 Clinical aspects of glucocorticoids 692

Patrick97397.indb xx 11/28/2012 9:11:53 PM Acronyms and abbreviations

Note: Abbreviations for amino acids are given in Appendix 1

5-HT 5-hydroxytryptamine (serotonin) dATP deoxyadenosine triphosphate 7-ACA 7-aminocephalosporinic acid DCC dicyclohexylcarbodiimide 6-APA 6-aminopenicillanic acid dCTP Deoxycytosine triphosphate ACE angiotensin-converting enzyme DG diacylglycerol ACh acetylcholine dGTP deoxyguanosine triphosphate AChE acetylcholinesterase DHFR dihydrofolate reductase ACT artemisinin combination therapy DMAP dimethylaminopyridine ADAPT antibody-directed abzyme prodrug therapy DNA deoxyribonucleic acid ADEPT antibody-directed enzyme prodrug therapy DOR delta opioid receptor ADH alcohol dehydrogenase dsDNA double-stranded DNA ADME absorption, distribution, metabolism, dsRNA double-stranded RNA excretion dTMP deoxythymidylate monophosphate ADP adenosine diphosphate dTTP deoxythymidylate triphosphate AIC 5-aminoimidazole-4-carboxamide dUMP deoxyuridylate monophosphate

AIDS acquired immune defi ciency syndrome EC 50 concentration of drug required to produce AML acute myeloid leukaemia 50% of the maximum possible eff ect ′ AMP adenosine 5 -monophosphate E s Taft ’s steric factor AT angiotensin EGF epidermal growth factor ATP adenosine 5′-triphosphate EGF-R epidermal growth factor receptor AUC area under the curve EMEA European Agency for the Evaluation of cAMP cyclic AMP Medicinal Products BuChE butylcholinesterase EPC European Patent Convention CCK cholecystokinin EPO European Patent Offi ce CDKs cyclin-dependent kinases FDA US Food and Drug Administration CETP cholesteryl ester transfer protein FdUMP fl uorodeoxyuracil monophosphate cGMP cyclic GMP FGF fi broblast growth factor CHO cells Chinese hamster ovarian cells FGF-R fi broblast growth factor receptor

CKIs cyclin-dependent kinase inhibitors FH 4 tetrahydrofolate CLogP calculated logarithm of the partition F oral bioavailability coeffi cient F inductive eff ect of an aromatic substituent CML chronic myeloid leukaemia in QSAR CMV cytomegalovirus F-SPE fl uorous solid phase extraction CNS central nervous system FLOG fl exible ligands orientated on grid CoA coenzyme A FPGS folylpolyglutamate synthetase CoMFA comparative molecular fi eld analysis FPP farnesyl diphosphate COMT catechol O-methyltransferase FT farnesyl transferase COX cyclooxygenase FTI farnesyl transferase inhibitor CSD Cambridge Structural Database G-Protein guanine nucleotide binding protein CYP enzymes that constitute the cytochrome GABA γ-aminobutyric acid P450 family GAP GTPase activating protein D-Receptor dopamine receptor GCP Good Clinical Practice

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GDEPT gene-directed enzyme prodrug therapy IUPAC International Union of Pure and Applied GDP guanosine diphosphate Chemistry GEF guanine nucleotide exchange factors IV intravenous K GGTase geranylgeranyltransferase D dissociation binding constant K GH growth hormone i inhibition constant K GIT gastrointestinal tract M Michaelis constant GLP Good Laboratory Practice KOR kappa opioid receptor GMC General Medical Council LAAM L-α-acetylmethadol GMP Good Manufacturing Practice LD 50 lethal dose required to kill 50% of a test GMP guanosine monophosphate sample of animals GnRH gonadotrophin-releasing hormone LDH lactate dehydrogenase gp glycoprotein LH luteinizing hormone GTP guanosine triphosphate LHRH luteinizing hormone-releasing hormones h-PEPT human intestinal proton-dependent LipE lipophilic effi ciency oligopeptide transporter Log P logarithm of the partition coeffi cient H-receptor histamine receptor LDL low density lipoprotein HA hemagglutinin LUMO lowest unoccupied molecular orbital HAART highly active antiretroviral therapy M-receptor muscarinic receptor HAMA human anti-mouse antibodies MAA Marketing Authorization Application HBA hydrogen bond acceptor MAB monoclonal antibody HBD hydrogen bond donor MAO monoamine oxidase HCV hepatitis C virus MAOI monoamine oxidase inhibitor HDL high density lipoprotein MAOS microwave assisted organic synthesis HERG human ether-a-go-go related gene MAP mitogen-activated protein HIF hypoxia-inducible factor MAPK mitogen-activated protein kinases HIV human immunodefi ciency virus MCH-R melanin-concentrating hormone receptor HMG- 3-hydroxy-3-methylglutaryl-coenzyme A MDR multidrug resistance SCoA MDRTB multidrug-resistant tuberculosis HMGR 3-hydroxy-3-methylglutaryl-coenzyme A MEP molecular electrostatic potential reductase miRNA micro RNA HOMO highest occupied molecular orbital miRNP micro RNA protein HPLC high-performance liquid chromatography MMP matrix metalloproteinase HPMA N -(2-hydroxypropyl)methacrylamide MMPI matrix metalloproteinase inhibitor HPT human intestinal di-/tripeptide transporter MOR mu opioid receptor HRV human rhinoviruses MR molar refractivity HSV herpes simplex virus mRNA messenger RNA HTS high-throughput screening MRSA methicillin-resistant Staphylococcus aureus

IC 50 concentration of drug required to inhibit a MTDD multi-target drug discovery target by 50% mTRKI multi-tyrosine receptor kinase inhibitor IGF-1R insulin growth factor 1 receptor MWt molecular weight IND Investigational Exemption to a New Drug N-receptor nicotinic receptor Application NA neuraminidase or noradrenaline + IP 3 inositol triphosphate NAD / nicotinamide adenine dinucleotide IPER International Preliminary Examination NADH Report NADP +/ nicotinamide adenine dinucleotide IRB Institutional Review Board NADPH phosphate ISR International Search Report NAG N -acetylglucosamine ITC isothermal titration calorimetry NAM N-acetylmuramic acid

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NCE new chemical entity RMSD root mean square distance NDA New Drug Application rRNA ribosomal RNA NICE National Institute for Health and Clinical RNA ribonucleic acid Excellence s standard error of estimate or standard NMDA N-methyl-D-aspartate deviation NME new molecular entity SAR structure–activity relationships NMR nuclear magnetic resonance SCAL safety-catch acid-labile linker NNRTI non-nucleoside reverse transcriptase SCF stem cell factor inhibitor SCID severe combined immunodefi ciency NO nitric oxide disease NOR nociceptin opioid receptor SKF Smith-Kline and French NOS nitric oxide synthase SNRI selective noradrenaline reuptake inhibitors NRTI nucleoside reverse transcriptase inhibitor siRNA small inhibitory RNA NSAID non-steroidal anti-infl ammatory drug snRNA small nuclear RNA NVOC nitroveratryloxycarbonyl SOP standard operating procedure ORL1 opioid receptor-like receptor SPA scintillation proximity assay P partition coeffi cient SPE solid phase extraction PABA p-aminobenzoic acid SPOS solution phase organic synthesis PBP penicillin binding protein SPR surface plasmon resonance PCP phencyclidine, otherwise known as ‘angel ssDNA single-stranded DNA dust’ SSRI selective serotonin reuptake inhibitor PCT patent cooperation treaty ssRNA single-stranded RNA PDB protein data bank TB tuberculosis PDE phosphodiesterase TCA tricyclic antidepressants PDGF platelet-derived growth factor TFA trifl uoroacetic acid PDGF-R platelet-derived growth factor receptor TGF-α transforming growth factor-α PDT photodynamic therapy TGF-β transforming growth factor-β PEG polyethylene glycol THF tetrahydrofuran PGE prostaglandin E TM transmembrane PGF prostaglandin F TNF tumour necrosis factor

PIP2 phosphatidylinositol diphosphate TNF-R tumour necrosis factor receptor PI protease inhibitor TNT trinitrotoluene PKA protein kinase A TRAIL TNF-related apoptosis-inducing ligand PKB protein kinase B TRIPS trade related aspects of intellectual prop- PKC protein kinase C erty rights PLC phospholipase C tRNA transfer RNA PLS partial least squares UTI urinary tract infection PPBI protein–protein binding inhibitor vdW van der Waals PPI proton pump inhibitor VEGF vascular endothelial growth factor PPts pyridinium 4-toluenesulfonate VEGF-R vascular endothelial growth factor receptor QSAR quantitative structure–activity relationships VIP vasoactive intestinal peptide r regression or correlation coeffi cient VOC–Cl vinyloxycarbonyl chloride R resonance eff ect of an aromatic substituent VRE vancomycin-resistant enterococci in QSAR VRSA vancomycin-resistant Staphylococci aureus RES reticuloendothelial system VZV varicella-zoster viruses RFC reduced folate carrier WHO World Health Organization RISC RNA induced silencing complex WTO World Trade Organization

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