Medicinal Chemistry: An Introduction, 2nd Edition

Preface to the First Edition xv

Preface to the Second Edition xvii

Acknowledgements xix

Abbreviations xxi

1 An introduction to drugs, their action and discovery 1

1.1 Introduction 1

1.2 What are drugs and why do we need new ones? 1

1.3 Drug discovery and design: a historical outline 3

1.3.1 The general stages in modern-day drug discovery and design 7

1.4 Leads and analogues: some desirable properties 9

1.4.1 Bioavailability 9

1.4.2 Solubility 10

1.4.3 Structure 10

1.4.4 Stability 11

1.5 Sources of leads and drugs 14

1.5.1 Ethnopharmaceutical sources 15

1.5.2 Plant sources 15

1.5.3 Marine sources 17

1.5.4 Microorganisms 18

1.5.5 Animal sources 20

1.5.6 Compound collections, data bases and synthesis 20

1.5.7 The pathology of the diseased state 21

1.5.8 Market forces and ‘me-too drugs’ 21

1.6 Methods and routes of administration: the pharmaceutical phase 21

1.7 Introduction to drug action 24

1.7.1 The pharmacokinetic phase (ADME) 25

1.7.2 The pharmacodynamic phase 32

1.8 Classification of drugs 33

1.8.1 Chemical structure 33

1.8.2 Pharmacological action 34

1.8.3 Physiological classification 34

1.8.4 Prodrugs 35

1.9 Questions 35

2 Drug structure and solubility 37

2.1 Introduction 37

2.2 Structure37

2.3 Stereochemistry and drug design 38

2.3.1 Structurally rigid groups 38

2.3.2 Conformation 39

2.3.3 Configuration 41

2.4 Solubility 44

2.4.1 Solubility and the physical nature of the solute 44

2.5 Solutions 46

2.6 The importance of water solubility 47

2.7 Solubility and the structure of the solute 49

2.8 Salt formation 50

2.9 The incorporation of water solubilising groups in a structure 52

2.9.1 The type of group 52

2.9.2 Reversible and irreversible groups 53

2.9.3 The position of the water solubilising group 53

2.9.4 Methods of introduction 54

2.9.5 Improving lipid solubility 59

2.10 Formulation methods of improving water solubility 59

2.10.1 Cosolvents 59

2.10.2 Colloidal solutions 59

2.10.3 Emulsions 60

2.11 The effect of pH on the solubility of acidic and basic drugs 61

2.12 Partition 63

2.12.1 Practical determination of partition coefficients 65

2.12.2 Theoretical determination of partition coefficients 66

2.13 Surfactants and amphiphiles 66

2.13.1 Drug solubilisation 69

2.13.2 Mixed micelles as drug delivery systems 71

2.13.3 Vesicles and liposomes 72

2.14 Questions 72

3 Structure–activity and quantitative structure relationships 75

3.1 Introduction 75

3.2 Structure–activity relationship (SAR) 76

3.3 Changing size and shape 77

3.3.1 Changing the number of methylene groups in chains and rings 77

3.3.2 Changing the degree of unsaturation 78

3.3.3 Introduction or removal of a ring system 78

3.4 Introduction of new substituents 80

3.4.1 Methyl groups 81

3.4.2 Halogen groups 83

3.4.3 Hydroxy groups 84

3.4.4 Basic groups 84

3.4.5 Carboxylic and sulphonic acid groups 85

3.4.6 Thiols, sulphides and other sulphur groups 85

3.5 Changing the existing substituents of a lead 86

3.6 Case study: a SAR investigation to discover potent geminal bisphosphonates 87

3.7 Quantitative structure–activity relationship (QSAR) 90

3.7.1 Regression analysis 93

3.7.2 The lipophilic parameters 94

3.7.3 Electronic parameters 99

3.7.4 Steric parameters 102

3.8 Questions 110

4 Computer-aided drug design 113

4.1 Introduction 113

4.1.1 Models 114

4.1.2 Molecular modelling methods 115

4.1.3 Computer graphics 116

4.2 Molecular mechanics 117

4.2.1 Creating a molecular model using molecular mechanics 120

4.3 Molecular dynamics 123

4.3.1 Conformational analysis 124

4.4 Quantum mechanics 124

4.5 Docking 127

4.5.1 De novo design 128

4.6 Comparing three-dimensional structures by the use of overlays 130

4.6.1 An example of the use of overlays 132

4.7 Pharmacophores and some of their uses 133

4.7.1 High-resolution X-ray crystallography or NMR 133

4.7.2 Analysis of the structures of different ligands 134

4.8 Modelling protein structures 135

4.9 Three-dimensional QSAR 136

4.9.1 Advantages and disadvantages 140

4.10 Other uses of computers in drug discovery 141

4.11 Questions 143

5 Combinatorial chemistry 145

5.1 Introduction 145

5.1.1 The design of combinatorial syntheses 147

5.1.2 The general techniques used in combinatorial synthesis 148

5.2 The solid support method 148

5.2.1 General methods in solid support combinatorial chemistry 150

5.2.2 Parallel synthesis 152

5.2.3 Furka’s mix and split technique 155

5.3 Encoding methods 157

5.3.1 Sequential chemical tagging 157

5.3.2 Still’s binary code tag system 160

5.3.3 Computerised tagging 161

5.4 Combinatorial synthesis in solution 161

5.4.1 Parallel synthesis in solution 162

5.4.2 The formation of libraries of mixtures 163

5.4.3 Libraries formed using monomethyl polyethylene glycol (OMe-PEG) 164

5.4.4 Libraries produced using dendrimers as soluble supports 164

5.4.5 Libraries formed using fluorocarbon reagents 165

5.4.6 Libraries produced using resin-bound scavenging agents 166

5.4.7 Libraries produced using resin-bound reagents 168

5.4.8 Resin capture of products 168

5.5 Deconvolution 169

5.6 High-throughput screening (HTS) 170

5.6.1 Biochemical assays 171

5.6.2 Whole cell assays 173

5.6.3 Hits and hit rates 173

5.7 Automatic methods of library generation and analysis 174

5.8 Questions 175

6 Drugs from natural sources 177

6.1 Introduction 177

6.2 Bioassays 179

6.2.1 Screening tests 180

6.2.2 Monitoring tests 183

6.3 Dereplication 185

6.4 Structural analysis of the isolated substance 186

6.5 Active compound development 188

6.6 Extraction procedures 189

6.6.1 General considerations 190

6.6.2 Commonly used methods of extraction 191

6.6.3 Cleaning up procedures 195

6.7 Fractionation methods 195

6.7.1 Liquid–liquid partition 196

6.7.2 Chromatographic methods 199

6.7.3 Precipitation 200

6.7.4 Distillation 200

6.7.5 Dialysis 202

6.7.6 Electrophoresis 202

6.8 Case history: the story of Taxol 202

6.9 Questions 206

7 Biological membranes 207

7.1 Introduction 207

7.2 The plasma membrane 208

7.2.1 Lipid components 209

7.2.2 Protein components 211

7.2.3 The carbohydrate component 213

7.2.4 Similarities and differences between plasma membranes in different cells 213

7.2.5 Cell walls 214

7.2.6 Bacterial cell exterior surfaces 217

7.2.7 Animal cell exterior surfaces 218

7.2.8 Virus 218

7.2.9 Tissue 219

7.2.10 Human skin 219

7.3 The transfer of species through cell membranes 220

7.3.1 Osmosis 220

7.3.2 Filtration 221

7.3.3 Passive diffusion 221

7.3.4 Facilitated diffusion 223

7.3.5 Active transport 223

7.3.6 Endocytosis 224

7.3.7 Exocytosis 225

7.4 Drug action that affects the structure of cell membranes and walls 225

7.4.1 Antifungal agents 226

7.4.2 Antibacterial agents (antibiotics) 230

7.4.3 Local anaesthetics 244

7.5 Questions 249

8 Receptors and messengers 251

8.1 Introduction 251

8.2 The chemical nature of the binding of ligands to receptors 252

8.3 Structure and classification of receptors 254

8.4 General mode of operation 256

8.4.1 Superfamily Type 1 259

8.4.2 Superfamily Type 2 260

8.4.3 Superfamily Type 3 263

8.4.4 Superfamily Type 4 264

8.5 Ligand–response relationships 265

8.5.1 Experimental determination of ligand concentration–response curves 266

8.5.2 Agonist concentration–response relationships 267

8.5.3 Antagonist concentration–receptor relationships 268

8.5.4 Partial agonists 271

8.5.5 Desensitisation 272

8.6 Ligand–receptor theories 272

8.6.1 Clark’s occupancy theory 272

8.6.2 The rate theory 277

8.6.3 The two-state model 278

8.7 Drug action and design 279

8.7.1 Agonists 279

8.7.2 Antagonists 281

8.7.3 Citalopram, an antagonist antidepressant discovered by a rational approach 282

8.7.4 b-Blockers 285

8.8 Questions 289

9 Enzymes 291

9.1 Introduction 291

9.2 Classification and nomenclature 293

9.3 Active sites and catalytic action 295

9.3.1 Allosteric activation 297

9.4 Regulation of enzyme activity 298

9.4.1 Covalent modification 298

9.4.2 Allosteric control 298

9.4.3 Proenzyme control 300

9.5 The specific nature of enzyme action 300

9.6 The mechanisms of enzyme action 302

9.7 The general physical factors affecting enzyme action 302

9.8 Enzyme kinetics 303

9.8.1 Single substrate reactions 303

9.8.2 Multiple substrate reactions 305

9.9 Enzyme inhibitors 306

9.9.1 Reversible inhibitors 307

9.9.2 Irreversible inhibition 312

9.10 Transition state inhibitors 318

9.11 Enzymes and drug design: some general considerations 320

9.12 Examples of drugs used as enzyme inhibitors 321

9.12.1 Sulphonamides 321

9.12.2 Captopril and related drugs 323

9.12.3 Statins 326

9.13 Enzymes and drug resistance 329

9.13.1 Changes in enzyme concentration 330

9.13.2 An increase in the production of the substrate 331

9.13.3 Changes in the structure of the enzyme 331

9.13.4 The use of an alternative metabolic pathway 332

9.14 Ribozymes 332

9.15 Questions 332

10 Nucleic acids 335

10.1 Introduction 335

10.2 Deoxyribonucleic acid (DNA) 336

10.2.1 Structure 337

10.3 The general functions of DNA 338

10.4 Genes 339

10.5 Replication 340

10.6 Ribonucleic acid (RNA) 341

10.7 Messenger RNA (mRNA) 342

10.8 Transfer RNA (tRNA) 343

10.9 Ribosomal RNA (rRNA) 345

10.10 Protein synthesis 345

10.10.1 Activation 345

10.10.2 Initiation 346

10.10.3 Elongation 347

10.10.4 Termination 348

10.11 Protein synthesis in prokaryotic and eukaryotic cells 348

10.11.1 Prokaryotic cells 348

10.11.2 Eukaryotic cells 350

10.12 Bacterial protein synthesis inhibitors (antimicrobials) 350

10.12.1 Aminoglycosides 351

10.12.2 Chloramphenicol 355

10.12.3 Tetracyclines 356

10.12.4 Macrolides 359

10.12.5 Lincomycins 360

10.13 Drugs that target nucleic acids 362

10.13.1 Antimetabolites 362

10.13.2 Enzyme inhibitors 368

10.13.3 Intercalating agents 372

10.13.4 Alkylating agents 374

10.13.5 Antisense drugs 377

10.13.6 Chain cleaving agents 379

10.14 Viruses 380

10.14.1 Structure and replication 380

10.14.2 Classification 381

10.14.3 Viral diseases 383

10.14.4 Antiviral drugs 384

10.15 Recombinant DNA technology (genetic engineering) 389

10.15.1 Gene cloning 389

10.15.2 Medical applications 392

10.16 Questions 401

11 Pharmacokinetics 403

11.1 Introduction 403

11.1.1 General classification of pharmacokinetic properties 405

11.1.2 Drug regimens 405

11.1.3 The importance of pharmacokinetics in drug discovery 406

11.2 Drug concentration analysis and its therapeutic significance 407

11.3 Pharmacokinetic models 409

11.4 Intravascular administration 411

11.4.1 Distribution 412

11.5 Extravascular administration 425

11.5.1 Dissolution 428

11.5.2 Absorption 429

11.5.3 Single oral dose 430

11.5.4 The calculation of tmax and Cmax 433

11.5.5 Repeated oral doses 434

11.6 The use of pharmacokinetics in drug design 435

11.7 Extrapolation of animal experiments to humans 435

11.8 Questions 436

12 Drug metabolism 439

12.1 Introduction 439

12.1.1 The stereochemistry of drug metabolism 439

12.1.2 Biological factors affecting metabolism 440

12.1.3 Environmental factors affecting metabolism 443

12.1.4 Species and metabolism 443

12.1.5 Enzymes and metabolism 443

12.2 Secondary pharmacological implications of metabolism 443

12.2.1 Inactive metabolites 444

12.2.2 Metabolites with a similar activity to the drug 444

12.2.3 Metabolites with a dissimilar activity to the drug 444

12.2.4 Toxic metabolites 445

12.3 Sites of action 445

12.4 Phase I metabolic reactions 446

12.4.1 Oxidation 446

12.4.2 Reduction 448

12.4.3 Hydrolysis 448

12.4.4 Hydration 449

12.4.5 Other Phase I reactions 449

12.5 Examples of Phase I metabolic reactions 449

12.6 Phase II metabolic routes 454

12.7 Pharmacokinetics of metabolites 457

12.8 Drug metabolism and drug design 458

12.9 Prodrugs 460

12.9.1 Bioprecursor prodrugs 461

12.9.2 Carrier prodrugs 462

12.9.3 Photoactivated prodrugs 464

12.9.4 The design of carrier prodrug systems for specific purposes 465

12.10 Questions 475

13 Complexes and chelating agents 477

13.1 Introduction 477

13.2 The shapes and structures of complexes 478

13.2.1 Ligands 479

13.2.2 Bridging ligands 483

13.2.3 Metal–metal bonds 483

13.2.4 Metal clusters 483

13.3 Metal–ligand affinities 485

13.3.1 Affinity and equilibrium constants 485

13.3.2 Hard and soft acids and bases 487

13.3.3 The general medical significance of complex stability 488

13.4 The general roles of metal complexes in biological processes 488

13.5 Therapeutic uses 491

13.5.1 Metal poisoning 491

13.5.2 Anticancer agents 494

13.5.3 Antiarthritics 497

13.5.4 Antimicrobial complexes 498

13.5.5 Photoactivated metal complexes 499

13.6 Drug action and metal chelation 501

13.7 Questions 501

14 Nitric oxide 503

14.1 Introduction 503

14.2 The structure of nitric oxide 503

14.3 The chemical properties of nitric oxide 504

14.3.1 Oxidation 505

14.3.2 Salt formation 506

14.3.3 Reaction as an electrophile 507

14.3.4 Reaction as an oxidising agent 507

14.3.5 Complex formation 508

14.3.6 Nitric oxide complexes with iron 508

14.3.7 The chemical properties of nitric oxide complexes 510

14.3.8 The chemistry of related compounds 512

14.4 The cellular production and role of nitric oxide 514

14.4.1 General mode of action 516

14.4.2 Suitability of nitric oxide as a chemical messenger 518

14.4.3 Metabolism 518

14.5 The role of nitric oxide in physiological and pathophysiological states 519

14.5.1 The role of nitric oxide in the cardiovascular system 519

14.5.2 The role of nitric oxide in the nervous system 520

14.5.3 Nitric oxide and diabetes 522

14.5.4 Nitric oxide and impotence 522

14.5.5 Nitric oxide and the immune system 523

14.6 Therapeutic possibilities 524

14.6.1 Compounds that reduce nitric oxide generation 524

14.6.2 Compounds that supply nitric oxide 526

14.6.3 The genetic approach 529

14.7 Questions 529

15 An introduction to drug and analogue synthesis 531

15.1 Introduction 531

15.2 Some general considerations 532

15.2.1 Starting materials 532

15.2.2 Practical considerations 532

15.2.3 The overall design 532

15.2.4 The use of protecting groups 533

15.3 Asymmetry in syntheses 534

15.3.1 The use of non-stereoselective reactions to produce stereospecific centres 535

15.3.2 The use of stereoselective reactions to produce stereogenetic centres 535

15.3.3 General methods of asymmetric synthesis 541

15.3.4 Methods of assessing the purity of stereoisomers 547

15.4 Designing organic syntheses 548

15.4.1 An introduction to the disconnection approach 548

15.4.2 Convergent synthesis 554

15.5 Partial organic synthesis of xenobiotics 556

15.6 Questions 557

16 Drug development and production 559

16.1 Introduction 559

16.2 Chemical development 560

16.2.1 Chemical engineering issues 561

16.2.2 Chemical plant: health and safety considerations 562

16.2.3 Synthesis quality control 563

16.2.4 A case study 563

16.3 Pharmacological and toxicological testing 565

16.4 Drug metabolism and pharmacokinetics 569

16.5 Formulation development 570

16.6 Production and quality control 570

16.7 Patent protection 571

16.8 Regulation 572

16.9 Questions 573

Selected further reading 575

Answers to questions 579

Index 601