An Intro To Med Chem 5th Ed.pdf - An Introduction to...

This preview shows page 1 out of 811 pages.

Unformatted text preview: An Introduction to Medicinal Chemistry FIFTH EDITION Graham L. Patrick 1 Preface This text is aimed at undergraduates and postgraduates who have a basic grounding in chemistry and are studying a module or degree in medicinal chemistry. It attempts to convey, in a readable and interesting style, an understanding about drug design and the molecular mechanisms by which drugs act in the body. In so doing, it highlights the importance of medicinal chemistry in all our lives and the fascination of working in a field which overlaps the disciplines of chemistry, biochemistry, physiology, microbiology, cell biology, and pharmacology. Consequently, the book is of particular interest to students who might be considering a future career in the pharmaceutical industry. New to this edition Following the success of the first four editions, as well as useful feedback from readers, there has been some reorganization and updating of chapters, especially those in Part E. Chapters have been modified, as appropriate, to reflect contemporary topics and teaching methods. This includes: • new coverage of 99 drugs not featured in the previous edition; • six new boxes, covering topics such ‘Cyclodextrins as drug scavengers’, ‘The structure-based drug design of crizotinib’, and ‘Designing a non-steroidal glucocorticoid agonist’; • a new case study on steroidal anti-inflammatory agents; • over 25 new sections, providing additional depth in subject areas including ‘Tethers and anchors’ and ‘Short-acting β-blockers’; • additional end-of-chapter questions; • current reference lists. We have also made significant changes to the Online Resource Centre, adding 40 molecular modelling exercises and 16 web articles. The structure of the book Following the introductory chapter, the book is divided into five parts. • Part A contains six chapters that cover the structure and function of important drug targets, such as recep- • • • • tors, enzymes, and nucleic acids. Students with a strong background in biochemistry will already know this material, but may find these chapters a useful revision of the essential points. Part B covers pharmacodynamics in Chapters 7–10 and pharmacokinetics in Chapter 11. Pharmacodynamics is the study of how drugs interact with their molecular targets and the consequences of those interactions. Pharmacokinetics relates to the issues involved in a drug reaching its target in the first place. Part C covers the general principles and strategies involved in discovering and designing new drugs and developing them for the marketplace. Part D looks at particular ‘tools of the trade’ which are invaluable in drug design, i.e. QSAR, combinatorial synthesis, and computer-aided design. Part E covers a selection of specific topics within medicinal chemistry—antibacterial, antiviral and anticancer agents, cholinergics and anticholinesterases, adrenergics, opioid analgesics, and antiulcer agents. To some extent, those chapters reflect the changing emphasis in medicinal chemistry research. Antibacterial agents, cholinergics, adrenergics, and opioids have long histories and much of the early development of these drugs relied heavily on random variations of lead compounds on a trial and error basis. This approach was wasteful but it led to the recognition of various design strategies which could be used in a more rational approach to drug design. The development of the anti-ulcer drug cimetidine (Chapter 25) represents one of the early examples of the rational approach to medicinal chemistry. However, the real revolution in drug design resulted from giant advances made in molecular biology and genetics which have provided a detailed understanding of drug targets and how they function at the molecular level. This, allied to the use of molecular modelling and X-ray crystallography, has revolutionized drug design. The development of protease inhibitors as antiviral agents (Chapter 20), kinase inhibitors as anticancer agents (Chapter 21), and the statins as cholesterollowering agents (Case study 1) are prime examples of the modern approach. G. L. P. November 2012 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. Emboldened key words Terminology is emboldened and defined in a glossary at the end of the book, helping you to become familiar with the language of medicinal chemistry. Boxes Boxes are used to present in-depth material and to explore how the concepts of medicinal chemistry are applied in practice. 1.3.1 Electrostatic or ionic bonds An ionic or electrostatic bond is the strongest of the intermolecular bonds (20–40 kJ mol−1) and takes place between groups that have opposite charges, such as a carboxylate ion and an aminium ion (Fig. 1.5). The strength of the interaction is inversely proportional to the distance between the two charged atoms and it is also dependent on the nature of the environment, being BOX 3.1 The external control of enzymes by nitric oxide The external control of enzymes is usually initiated by external chemical messengers which do not enter the cell. However, there is an exception to this. It has been discovered that cells can generate the gas nitric oxide by the reaction sequence shown in Fig. 1, catalysed by the enzyme nitric oxide synthase. Because nitric oxide is a gas, it can diffuse easily through cell membranes into target cells. There, it activates enzymes H2N Key points one or more of the following interactions, but not necessarily all of them. present in the drug can be important in forming intermolecular bonds with the target binding site. If they do so, they are called binding groups. However, the carbon skeleton of the drug also plays an important role in binding the drug to its target through van der Waals interactions. As far as the target binding site is concerned, it too contains functional groups and carbon skeletons which can form intermolecular bonds with ‘visiting’ drugs. The specific regions where this takes place are known as binding regions. The study of how drugs interact with their targets through binding interactions and produce a pharmacological effect is known as pharmacodynamics. CO2H H2N CO2H H2N End-of-chapter questions allow you to test your understanding and apply concepts presented in the chapter. Further reading Selected references allow you to easily research those topics that are of particular interest to you. Appendix The appendix includes an index of drug names and their corresponding trade names, and an extensive glossary. CO2H their pharmacological effect. By chemical structure Many drugs which have a common skeleton are grouped together, for example penicillins, barbiturates, opiates, steroids, and catecholamines. In some cases, this is a useful classification as the biological activity and mechanism of action is the same for the structures involved, for example the antibiotic activity of penicillins. However, not all compounds with similar chemical structures have the same biological action. For example, steroids share a similar tetracyclic structure, but they have very different effects in the body. In this text, various groups of structurally-related drugs are discussed, KEY POINTS Summaries at the end of major sections within chapters highlight and summarize key concepts and provide a basis for revision. Questions called cyclases to generate cyclic GMP from GTP (Fig. 2). Cyclic GMP then acts as a secondary messenger to influence other reactions within the cell. By this process, nitric oxide has an influence on a diverse range of physiological processes, including blood pressure, neurotransmission, and immunological defence mechanisms. QUESTIONS 1. Enzymes can be used in organic synthesis. For example, the reduction of an aldehyde is carried out using aldehyde dehydrogenase. Unfortunately, this reaction requires the use of the cofactor NADH, which is expensive and is used up in the reaction. If ethanol is added to the reaction, only 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 acetylcholinesterase. Suggest what sort of binding Create a Michaelis Menton plot and a Lineweaver-Burk plot. Use both plots to calculate the values of KM and the estradiol in the presence of the cofactor NADH. The initial rate data for the enzyme-catalysed reaction in the absence of an inhibitor is as follows: Substrate concentration (10−2 mol dm−3) 5 10 25 50 100 FURTHER READING Navia, M. A. and Murcko, M. A. (1992) Use of structural information in drug design. Current Opinion in Structural Biology 2, 202–216. Teague, S. J. (2003) Implications of protein flexibility for drug discovery. Nature Reviews Drug Discovery 2, 527–541. Broadwith, P. (2010) Enzymes do the twist. Chemistry World. Available at: January/06011001.asp (last accessed 14 June 2012). Knowles, J. R. (1991) Enzyme catalysis: not different, just better. Science 350, 121–124. 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 1 Essential amino acids NON POLAR (hydrophobic) H H3N C H CO2 H3N C H H CO2 H3 N C CO2 H3N C H CO2 H3N C CO2 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: Student resources Lecturer resources Rotatable 3D structures For registered adopters of the book Web articles All these resources can be downloaded and are fully customizable, allowing them to be incorporated into your institution’s existing virtual learning environment. Links to where you can view the structures from the book in interactive rotating form. Developments in the field since the book published and further information that you may find of interest. Molecular modelling exercises Develop your molecular modelling skills, using Wavefunction’s SpartanTM software to answer the set questions. To answer all the questions, you will need the full version of Spartan, which is widely distributed at colleges and universities; check with your institution for access. You will be able to answer a selection of the questions and familiarize yourself with the basics using Spartan Student EditionTM. Students can purchase this from store.wavefun.com/product_p/SpStudent.htm. Enter the promotional code OUPAIMC to receive 20% discount for students using An Introduction to Medicinal Chemistry. For questions or support for SpartanTM, visit . Multiple choice questions Test yourself on the topics covered in the text and receive instant feedback. Test bank A bank of multiple choice questions, which can be downloaded and customized for your teaching. Answers Answers to end-of-chapter questions. Figures from the book All of the figures from the textbook are available to download electronically for use in lectures and handouts. PowerPoint slides PowerPoint slides are provided to help teach selected topics from the book. Acknowledgements The author and Oxford University Press would like to thank the following people who have given advice on the various editions of this textbook: Dr Lee Banting, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK Dr Don Green, Department of Health and Human Sciences, London Metropolitan University, UK Dr Mike Southern, Department of Chemistry, Trinity College, University of Dublin, Ireland Dr Mikael Elofsson (Assistant Professor), Department of Chemistry, Umeå University, Sweden Dr Ed Moret, Faculty of Pharmaceutical Sciences, Utrecht University, the Netherlands Professor John Nielsen, Department of Natural Sciences, Royal Veterinary and Agricultural University, Denmark Professor Henk Timmerman, Department of Medicinal Chemistry, Vrije Universiteit, the Netherlands Professor Nouri Neamati, School of Pharmacy, University of Southern California, USA Professor Kristina Luthman, Department of Chemistry, Gothenburg University, Sweden Professor Taleb Altel, College of Pharmacy, University of Sarjah, United Arab Emirates Professor Dirk Rijkers, Faculty of Pharmaceutical Sciences, Utrecht University, the Netherlands Dr Sushama Dandekar, Department of Chemistry, University of North Texas, USA Dr John Spencer, Department of Chemistry, University of Sussex, UK Dr Angeline Kanagasooriam, School of Physical Sciences, University of Kent at Canterbury, UK Dr A Ganesan, School of Chemistry, University of Southampton, UK Dr Rachel Dickens, Department of Chemistry, University of Durham, UK Dr Gerd Wagner, School of Chemical Sciences and Pharmacy, University of East Anglia, UK Dr Colin Fishwick, School of Chemistry, University of Leeds, UK Professor Paul O’Neil, Department of Chemistry, University of Liverpool, UK Professor Trond Ulven, Department of Chemistry, University of Southern Denmark, Denmark Professor Jennifer Powers, Department of Chemistry and Biochemistry, Kennesaw State University, USA Professor Joanne Kehlbeck, Department of Chemistry, Union College, USA Dr Robert Sinclair, Faculty of Pharmaceutical Sciences, University of British Columbia, Canada Professor John Carran, Department of Chemistry, Queen’s University, Canada Professor Anne Johnson, Department of Chemistry and Biology, Ryerson University, Canada Dr Jane Hanrahan, Faculty of Pharmacy, University of Sydney, Australia Dr Ethel Forbes, School of Science, University of West of Scotland, UK Dr Zoë Waller, School of Pharmacy, University of East Anglia, UK Dr Susan Matthews, School of Pharmacy, University of East Anglia, UK Professor Ulf Nilsson, Organic Chemistry, Lund University, Sweden Dr Russell Pearson, School of Physical and Geographical Sciences, Keele University, UK Dr Rachel Codd, Sydney Medical School, The University of Sydney, Australia Dr Marcus Durrant, Department of Chemical and Forensic Sciences, Northumbria University, UK Dr Alison Hill, College of Life and Environmental Sciences, University of Exeter, UK Dr Connie Locher, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Australia Dr Angeline Kanagasooriam, School of Physical Sciences, University of Kent, UK Jon Våbenø, Department of Pharmacy, University of Tromsø, Norway The author would like to express his gratitude to Dr John Spencer of the University of Sussex for coauthoring Chapter 16, the preparation of several web articles, and for feedback during the preparation of this fifth edition. Much appreciation is owed to Nahoum Anthony and Dr Rachel Clark of the Strathclyde Institute for Pharmaceutical and Biomedical Sciences at the University of Strathclyde for their assistance with creating Figures 2.9; Box 8.2, Figures 1 and 3; and Figures 17.9, 17.44, 20.15, 20.22, 20.54, and 20.55 from pdb files, some of which were obtained from the RSCB Protein Data Bank. Dr James Keeler of the Department of Chemistry, University of Cambridge, kindly generated the molecular models that appear on the book’s Online Resource Centre. Thanks also to Dr Stephen Bromidge of GlaxoSmithKline for permitting the description of his work on selective 5-HT2C antagonists, and for providing many of the diagrams for that web article. Finally, many thanks to Cambridge Scientific, Oxford Molecular, and Tripos for their advice and assistance in the writing of Chapter 17. Brief contents List of boxes Acronyms and abbreviations 1 Drugs and drug targets: an overview xix xxi 1 PART A Drug targets 2 Protein structure and function 17 3 Enzymes: structure and function 30 4 Receptors: structure and function 42 5 Receptors and signal transduction 58 6 Nucleic acids: structure and function 71 PART B Pharmacodynamics and pharmacokinetics 7 Enzymes as drug targets 87 8 Receptors as drug targets 102 9 Nucleic acids as drug targets 120 PART D Tools of the trade 16 Combinatorial and parallel synthesis 313 17 Computers in medicinal chemistry 337 18 Quantitative structure–activity relationships (QSAR) 383 ■ Case study 5: Design of a thymidylate synthase inhibitor 407 PART E Selected topics in medicinal chemistry 19 Antibacterial agents 413 20 Antiviral agents 468 21 Anticancer agents 514 22 Cholinergics, anticholinergics, and anticholinesterases 578 23 Drugs acting on the adrenergic nervous system 609 24 The opioid analgesics 632 25 Anti-ulcer agents 659 10 Miscellaneous drug targets 135 11 Pharmacokinetics and related topics 153 ■ Case study 6: Steroidal anti-inflammatory agents 689 178 ■ Case Study 7: Current research into antidepressant agents ■ Case study 1: Statins PART C Drug discovery, design, and development 12 Drug discovery: finding a lead 189 13 Drug design: optimizing target interactions 215 14 Drug design: optimizing access to the target 248 15 Getting the drug to market 274 ■ Case study 2: The design of angiotensinconverting enzyme (ACE) inhibitors 292 ■ Case study 3: Artemisinin and related antimalarial drugs 299 ■ Case study 4: The design of oxamniquine 305 700 Appendix 1 Essential amino acids Appendix 2 The standard genetic code Appendix 3 Statistical data for quantitative structure–activity relationships (QSAR) Appendix 4 The action of nerves Appendix 5 Microorganisms Appendix 6 Drugs and their trade names Appendix 7 Trade names and drugs Appendix 8 Hydrogen bonding interactions Appendix 9 Drug properties 705 706 707 711 715 717 722 728 730 Glossary General further reading Index 741 761 763 Contents List of boxes Acronyms and abbreviations 1 Drugs and drug targets: an overview xix xxi 1 1.1 What is a drug? 1 1.2 Drug targets 3 3 4 1.2.1 1.2.2 Cell structure Drug targets at the molecular level 1.3 Intermolecular bonding forces 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 Electrostatic or ionic bonds Hydrogen bonds Van der Waals interactions Dipole–dipole and ion–dipole interactions Repulsive interactions The role of water and hydrophobic interactions 1.4 Pharmacokinetic issues and medicines 5 5 6 8 8 9 10 11 1.5 Classification of drugs 11 1.6 Naming of drugs and medicines 12 PART A Drug targets 2 Protein structure and function 17 2.1 The primary structure of proteins 17 2.2 The secondary structure of proteins 18 18 18 18 2.2.1 2.2.2 2.2.3 The α-helix The β-pleated sheet The β-turn 2.3 The tertiary structure of proteins 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 Covalent bonds—disulphide links Ionic or electrostatic bonds Hydrogen bonds Van der Waals and hydrophobic interactions Relative importance of bonding interactions Role of the planar peptide bond 2.4 The quaternary structure of proteins 19 21 21 21 22 23 23 23 3.4 Substrate binding at an active site 32 3.5 The catalytic role of enzymes 32 32 33 34 35 35 35 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.5.6 Binding interactions Acid/base catalysis Nucleophilic groups Cofactors Naming and classification of enzymes Genetic polymorphism and enzymes 3.6 Regulation of enzymes 36 3.7 Isozymes 39 3.8 Enzyme kinetics The Michaelis-Menton equation Lineweaver-Burk plots 39 39 40 4 Receptors: structure and function 42 3.8.1 3.8.2 4.1 Role of the receptor 42 4.2 Neurotransmitters and hormones 42 4.3 Receptor types and subtypes 45 4.4 Receptor activation 45 4.5 How does the binding site change shape? 45 4.6 Ion channel receptors 47 47 48 49 49 4.6.1 4.6.2 4.6.3 4.6.4 General principles Structure Gating Ligand-gated and voltage-gated ion channels 4.7 G-protein-coupled receptors 4.7.1 4.7.2 4.7.3 4.7.4 General principles Structure The rhodopsin-like family of G-protein-coupled receptors Dimerization of G-coupled receptors 4.8 Kinase-linked receptors 4.8.1 4.8.2 4.8.3 4.8.4 General principles Structure of tyrosine kinase receptors Activation mechanism f...
View Full Document

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture