Graham L.Patrick An introduction to Medicinal Chemistry This text is aimed at undergraduates who have a basic grounding in chemistry and are interested in a future career in the pharmaceutical industry. It attempts to convey something of the fascination of working in a field which overlaps the disciplines of chemistry, biochemistry, cell biology, and pharmacology. No previous knowledge of biology is assumed and the first six chapters cover the basics of cell structure, proteins, and nucleic acids as applied to drug design. Chapters 7, 8, and 9 describe the general tactics employed in developing an effective drug and also the difficulties faced by the medicinal chemist in this task. Chapters 10, 11, and 12 cover three particular areas of medicinal chemistry and are representative of the classifications which prevail in medicinal chemistry. By doing this, it is hoped that the advantages and disadvantages of the various classification schemes are exemplified. The three areas of medicinal chemistry described in Chapters 10, 11, and 12 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 is wasteful and the future of medicinal chemistry lies in the rational design of drugs based on a firm understanding of their biology and chemistry. The development of the antiulcer drug cimetidine represents one of the best examples of the rational approach to medicinal chemistry and is covered in Chapter 13. Paisley G.L.P. June 1994 Oxford University Press, 1995

Contents
Classification of drugs	xiii
1.Drugs and the medicinal chemist	1
2.The why and the wherefore	9
2.1.Why should drugs work?	9
2.2.Where do drugs work?	9
3.Protein structure	15
3.1.The primary structure of proteins	15
3.2.The secondary structure of proteins	16
3.2.1.The alpha helix	16
3.2.2.The beta-pleated sheet	16
3.3.The tertiary structure of proteins	16
3.3.1.Covalent bonds	21
3.3.2.Ionic bonds	21
3.3.3.Hydrogen bonds	21
3.3.4.Van der Waals bonds	22
3.3.5.Repulsive forces	22
3.3.6.Relative importance of binding forces	23
3.4.The quaternary structure of proteins	25
3.5.Conclusion	26
4.Drug action at enzymes	27
4.1.Enzymes as catalysts	27
4.2.How do catalysts lower activation energies?	28
4.3.The active site of an enzyme	30
4.4.Substrate binding at an active site	31
4.4.1.The binding forces	31
4.4.2.Competitive (reversible) inhibitors	32
4.4.3.Non-competitive (irreversible) inhibitors	34
4.4.4. Non-competitive, reversible (allosteric) inhibitors	35
4.5.The catalytic role of enzymes	37
4.5.1.Binding interactions	37
4.5.2.Acid/base catalysis	39
4.5.3.Nucleophilic groups	39
4.6.Medicinal uses of enzyme inhibitors	44
5.Drug action at receptors	45
5.1.The receptor role	45
5.2.Neurotransmitters	47
5.3.Receptors	49
5.4 How does the message get received?	50
5.4.1.Ion channels and their control	50
5.4.2 Membrane-bound enzymes - activation/deactivation	52
5.5. How does a receptor change shape?	54
5.6. The design of agonists	56
5.6.1.Binding groups	57
5.6.2.Position of binding groups	58
5.6.3. Size and shape	60
5.7. The design of antagonists	61
5.7.1. Antagonists acting at the binding site	61
5.7.2. Antagonists acting outwith the binding site	62
5.8.Partial agonists	63
5.9.Desensitization	65
5.10. Tolerance and dependence	65
6. Nucleic acids	68
6.1. Structure of DNA	68
6.1.1.The primary structure of DNA	68
6.1.2. The secondary structure of DNA	70
6.1.3. The tertiary structure of DNA	71
6.2. Drugs acting on DNA	72
6.2.1.Intercalating agents	72
6.2.2.Alkylating agents	74
6.2.3.Drugs acting by chain "cutting"	76
6.3.Ribonucleic acid	77
6.4.Drugs acting on RNA	80
6.5.Summary	81
7. Drug development	82
7.1 Screening of natural products	82
7.2 Isolation and purification	83
7.3 Structure determination	83
7.4 Structure-activity relationships	84
7.4.1 The binding role of hydroxyl groups	86
7.4.2 The binding role of ammo groups	88
7.4.3 The binding role of aromatic rings	88
7.4.4 The binding role of double bonds	89
7.5 Synthetic analogues	89
7.5.1 Variation of substituents	90
7.5.2 Extension of the structure	92
7.5.3 Chain extensions/contractions	93
7.5.4 Ring expansions/contractions	93
7.5.5 Ring variations	93
7.5.6 Isosteres	94
7.5.7 Simplification of the structure	95
7.5.8 Rigidification of the structure	96
7.6. Receptor theories	97
7.7 The elements of luck and inspiration	101
7.8 Lead compounds	103
7.9.A case study - oxamniquine	104
8. Pharmacodynamics	111
8.1. Drug distribution and 'survival'	111
8.1.1.Chemical stability	112
8.1.2.Metabolic stability	112
8.1.3.Hydrophilic/hydrophobic balance	113
8.2.Drug dose levels	115
8.3.Drug design for pharmacokinetic problems	116
8.3.1.Variation of substituents	116
8.3.2.Stereoelectronic modifications	116
8.3.3.Metabolic blockers	117
8.3.4.Removal of susceptible metabolic groups	117
8.3.5.Prodrugs	119
8.3.6.Bioisosteres	123
8.3.7."Sentry" drugs - synergism	124
8.3.8."Search and destroy" drugs	125
8.3.9.Self-destruct drugs	126
8.3.10. Delivery systems	126
8.4. Testing of drugs	126
8.5.Neurotransmitters as drugs?	127
9. Quantitative structure-activity relationships (QSAR)	128
9.1.Introduction	128
9.2.Graphs and equations	129
9.3.Physicochemical properties	130
9.3.1.Hydrophobicity	130
9.3.2.Electronic effects	136
9.3.3.Steric factors	140
9.3.4.Other physicochemical parameters	141
9.4.Hansch equation	141
9.5.The Craig plot	143
9.6. The Topliss scheme	145
9.7.Bioisosteres	148
9.8.Planning a QSAR study	149
9.9.Case study	150
10. Antibacterial agents	154
10.1. The history of antibacterial agents	154
10.2. The bacterial cell	157
10.3.Mechanisms of antibacterial action	158
10.4.Antibacterial agents which act against cell metabolism (antimetabolites)	159
10.4.1.Sulf onamides	159
10.4.2.Examples of other antimetabolites	164
10.5. Antibacterial agents which inhibit cell wall synthesis	166
10.5.1.Penicillins	166
10.5.2.Cephalosporins	181
10.5.3.Novel p-lactam antibiotics	188
10.5.4.The mechanism of action of penicillins and cephalosporins	192
10.6. Antibacterial agents which act on the plasma membrane structure	195
10.7.Antibacterial agents which impair protein synthesis	198
10.7.1.Rifamycins	198
10.7.2.Aminoglycosides	199
10.7.3.Tetracyclines	199
10.7.4.Chloramphenicol	200
10.7.5.Macrolides	201
10.8. Agents which act on nucleic acid transcription and replication	201
10.8.1.Quinolones and fluoroquinolones	201
10.8.2.Aminoacridines	202
10.9.Drug resistance	203
10.9.1.Drug resistance by mutation	203
10.9.2.Drug resistance by genetic transfer	203
10.9.3.Other factors affecting drug resistance	204
11. The peripheral nervous system - cholinergics, anticholinergics, and anticholinesterases	205
11.1. The peripheral nervous system	206
11.2. Motor nerves of the peripheral nervous system	206
11.2.1.The somatic motor nervous system	207
11.2.2.The autonomic motor nervous system	207
11.3. The neurotransmitters	209
11.4.Actions of the peripheral nervous system	209
11.5.The cholinergic system	210
11.6.Agonists at the cholinergic receptor	212
11.7.Acetylcholine - structure, SAR, and receptor binding	214
11.8.The instability of acetylcholine	218
11.9.Design of acetylcholine analogues	219
11.9.1.Steric hindrance	219
11.9.2.Electronic effects	220
11.9.3.Combining steric and electronic effects	221
11.10 Clinical uses for cholinergic agonists	222
11.11 Antagonists of the muscarinic cholinergic receptor	222
11.11.1 Actions and uses of muscarinic antagonists	222
11.11.2 Muscarinic antagonists	223
11.12 Antagonists of the nicotinic cholinergic receptor	228
11.12.1.Applications of nicotinic antagonists	228
11.12.2. Nicotinic antagonists	229
11.13 Other cholinergic antagonists	233
11.14 The nicotinic receptor - structure	234
11.15 The muscarinic receptor - structure	234
11.16 Anticholinesterases and acetylcholinesterase	235
11.16.1 Effect of anticholinesterases	235
11.16.2 Structure of the acetylcholinesterase enzyme	236
11.16.3 The active site of acetylcholinesterase	236
11.17 An ticholinesterase drugs	238
11.17.1 The carbamates	238
11.17.2 Organophosphorus compounds	242
11.18 Pralidoxime - an organophosphate antidote	244
12. The opium analgesics	246
12.1.Introduction	246
12.2.Morphine	249
12.2.1.Structure and properties	249
12.2.2.Structure-activity relationships	250
12.3.Development of morphine analogues	255
12.3.1.Variation of substituents	256
12.3.2.Drug extension	256
12.3.3.Simplification or drug dissection	259
12.3.4.Rigidification	265
12.4 Receptor theory of analgesics	269
12.4.1.Beckett-Casy hypothesis	269
12.4.2.Multiple analgesic receptors	271
12.5.Agonists and antagonists	273
12.6.Enkephalins and endorphins	275
12.6.1.Naturally occurring enkephalins and endorphins	275
12.6.2.Analogues of enkephalins	275
12.7.Receptor mechanisms	276
12.7.1.The mu receptor ()	277
12.7.2.The kappa receptor (k)	278
12.7.3 The delta receptor ()	278
12.7.4 The sigma receptor ()	279
12.8 The future	279
13. Cimetidine - a rational approach to drug design	281
13.1.Introduction	281
13.2.In the beginning - ulcer therapy in 1964	282
13.3.Histamine	284
13.4.The theory - two histamine receptors?	284
13.5.Searching for a lead - histamine	285
13.6.Searching for a lead - Afa-guanylhistamine	286
13.7.Developing the lead - a chelation bonding theory	290
13.8.From partial agonist to antagonist - the development of burimamide	292
13.9.Development of metiamide	294
13.10.Development of cimetidine	298
13.11.Cimetidine	300
13.11.1.Biological activity of cimetidine	300
13.11.2.Structure and activity of cimetidine	301
13.11.3.Metabolism of cimetidine	301
13.12.Further studies - cimetidine analogues	302
13.12.1.Conformational isomers	302
13.12.2.Desolvation	303
13.13.Variation of the imidazole ring - ranitidine	308
13.14.Famotidine and nizatidine	309
13.15. H2 antagonists with prolonged activity	310
13.16.Comparison of HI and H2 antagonists	311
13.17.The H2 receptor and H2 antagonists	311
Appendix 1 The essential amino acids	313
Appendix 2 The action of nerves	314
Appendix 3 Secondary messengers	320
Appendix 4 Bacteria and bacterial nomenclature	326
Glossary	328
Further reading	330
Index	331

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