An Introduction to Medicinal

An Introduction to Medicinal Chemistry FIFTH EDITION Graham L. Patrick 1 Patrick97397.indb iii 11/28/2012 9:11:45 PM 1 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 anti cancer agents, cholinergics and anticholinest- re o 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.

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