MedicinalChemistry

An Introduction

Gareth ThomasUniversity of Portsmouth

John Wiley & Sons, Ltd 'Chichester • New York • Weinheim • Brisbane • Singapore • Toronto

Preface xxi

Acknowledgements xxiii

Abbreviations xxv

% Introduction 1l o t Introduction l

I o 2 What are drugs and why do we need new ones? l

l o j Drug discovery and design, a historical outline 3

1*4 Methods and routes of administration, the pharmaceutical phase 7

i o § Introduction to drug action 10

1.5.1 The pharmacokinetic phase 111.5.1.1 Absorption , 111.5.1.2 Distribution , 121.5.1.3 Metabolism 131.5.1.4 Elimination 13

1.5.2 Bioavailability of a drug 141.5.3 The pharmacodynamic phase 15

1 . 6 Classification of drugs 151.6.1 Chemical structure 151.6.2 Pharmacological action 161.6.3 Physiological classification 161.6.4 Prodrugs 17

toj Drug stability n

1 . 8 Sources of drugs 191.8.1 Plant sources .' 201.8.2 Marine sources - 211.8.3 Microorganisms 21

let": > Contents

1.8.4 Drug synthesis 221.8.5 Market forces and 'me-too drugs' 23

i > 9 Drug development and production 231.9.1 Trials and their significance 241.9.2 Scaling up for production 261.9.3 Production and quality control 261.9.4 Patent protection 27

l o t © Summary 28

l o l l Questions 29

21 Drug discovery by design 31

2 . 1 Introduction 31

2.2 Stereochemistry and drug design 332.2.1 Structurally rigid groups 332.2.2 Conformation 342.2.3 Configuration 36

2.3 Structure-activity relationships (SAR) 372.3.1 Changing size and shape > 38

2.3.1.1 Changing the number of methylene groups in a chain 392.3.1.2 Changing the degree of unsaturation 402.3.1.3 Introduction or removal of a ring system 40

2.3.2 Introduction of new substituents 422.3.2.1 Methyl groups 432.3.2.2 Halogen groups 452.3.2.3 Hydroxy groups 452.3.2.4 Basic groups 462.3.2.5 Carboxylic and sulphonic acid groups 472.3.2.6 Thiols, sulphides and other sulphur groups 47

2.3.3 Changing the existing substituents of a lead 47

2.4 Quantitative structure-activity relationships (QSAR) 492.4.1 The partition parameters 50

2.4.1.1 Partition coefficients (P) , 502.4.1.2 Lipophilic substituent constants (71) . 52

2.4.2 Electronic parameters 54

Contents

2.4.2.1 The Hammett constant (a) 542.4.3 Steric parameters 57

2.4.3.1 The Taft steric parameter (Es) 572.4.3.2 Molar refractivity (MR) 582.4.3.3 The other parameters 59

2.4.4 Hansch analysis 592.4.4.1 Craig plots 62

2.4.5 The Topliss decision tree 63

• 5 Computer-aided drug design 672.5.1 Modelling drug-receptor interactions 67

. 6 Combinatorial chemistry 692.6.1 Introduction 692.6.2 The basic concept of combinatorial chemistry 702.6.3 The design of combinatorial syntheses 702.6.4 The general techniques used in combinatorial synthesis 722.6.5 The solid support method 72

2.6.5.1 Parallel synthesis 76Fodor's method for parallel synthesis 78

2.6.5.2 Furka's mix and split technique 802.6.5.3 Sequential chemical tagging methods 812.6.5.4 Still's binary code tag system 842.6.5.5 Computerised tagging 85

2.6.6 Combinatorial synthesis in solution 862.6.7 Screening and deconvolution / 86

»7 Summary 88

M Questions 90

Drug solubility

. 1 Introduction3.1.1 The importance of water solubility

o2 The structure of bulk liquids3.2.1 The structure of water

»3 Solutions3.3.1 The nature of lipid solutions

Contents

3.3.2 The nature of aqueous solutions 973.3.2.1 Polar solutes 973.3.2.2 Non-polar solutes 98

| o 4 Solubility 993.4.1 Solids 100

3.4.1.2 Sparingly soluble substances that ionise in water 1013.4.2 Liquids 1033.4.3 The solubility of gases 105

| o5 Solubility and the structure of the solute 106

| o 6 Salt formation 107

| . J The incorporation of water-solubilising groups in a structure 1093.7.1 The type of group 1103.7.2 Reversible and irreversible groups 1103.7.3 The position of the water-solubilising group 1103.7.4 Methods of introduction 111

3.7.4.1 Carboxylic acid groups by alkylation 1113.7.4.2 Carboxylic acid groups by acylation 1123.7.4.3 Phosphate groups 1133.7.4.4 Sulphonic acid groups 1143.7.4.5 Incorporation of basic groups 1143.7.4.6 Polyhydroxy and ether residues 116

| o S Formulation methods of improving water solubility in.3.8.1 Cosolvents 1183.8.2 Colloidal solutions 1183.8.3 Emulsions 119

| . 9 The effect of the pH on the solubility of acidic and basic drugs 119

>1O Partition 1233.10.1 Theoretical determination of partition coefficients 124

Surfactants, structure and action 1253.11.1 Micelles . 127

3.11.1.1 Drug solubilisation , 1273.11.1.2 Mixed micelles as drug delivery systems 1293.11.1.3 Liposomes 129

Contents

3»12 Summary

3 oil 3 Questions

Biological membranes

Introduction

, 2 The plasma membrane4.2.1 Lipid components4.2.2 Protein components4.2.3 The carbohydrate component4.2.4 Similarities and differences between plasma membranes in different cells4.2.5 Cell walls

4.2.5.1 Bacterial cell walls4.2.6 Bacterial cell exterior surfaces4.2.7 Animal cell exterior surfaces4.2.8 Viruses4.2.9 Tissue4.2.10 Skin

=3 The transfer of species through cell membranes4.3.1 Osmosis4.3.2 Filtration /4.3.3 Passive diffusion4.3.4 Facilitated diffusion4.3.5 Active transport4.3.6 Endocytosis4.3.7 Exocytosis

»4 Drug action that affects the structure of cell membranes and walls4.4.1 Antifungal agents

4.4.1.1 Azoles4.4.1.2 Allylamines and related compounds4.4.1.3 Phenols

4.4.2 Antibacterial agents4.4.2.1 Ionophoric antibiotic action

Channel ionophoresCarrier ionophores ,

4.4.2.2 Cell wall synthesis inhibitionDrugs that inhibit the formation of the starting compounds

X j Contents

Drugs that inhibit the synthesis of the peptidoglycan chain 163Drugs that inhibit the cross-linking of the peptidoglycan chains 165

4.4.2.3 Surface-active agents 1694.4.3 Local anaesthetics 169

, § Summary 174

»6 Questions 176

Pharmacokinetics 179

Introduction 1795.1.1 General classification of pharmacokinetic properties 1815.1.2 Drug regimens 1815.1.3 The importance of pharmacokinetics in developing a drug 182

, 2 Drug concentration analysis and its therapeutic significance 183

>3 Pharmacokinetic models 185

»4 Intravascular administration 1875.4.1 Distribution 188

5.4.1.1 The binding of drugs to plasma proteins 1885.4.1.2 Intravenous injection (i.v.'bolus) 1895.4.1.3 Elimination and elimination half-life 190

Half-life (t1/2) 192Elimination rate constant 193

5.4.1.4 Clearance and its significance 1935.4.2 Intravenous infusion 198

Ȥ Extravascular administration 201Relative bioavailability 202Absolute bioavailability 203

5.5.1 Single oral dose 2045.5.2 The calculation of tmax and Cmax 2075.5.3 Repeated oral doses 208

. 6 The use of pharmacokinetics in drug design 209

o j Extrapolation of animal experiments to humans 210

Contents f; jtf

Summary 211

Questions 213

Enzymes 215

01 Introduction 215

. 2 Classification and nomenclature 217

03 Active sites and catalytic action 2196.3.1 Allosteric activation 221

04 Regulation of enzyme activity 2216.4.1 Covalent modification 2226.4.2 Allosteric control 222

e§ The specific nature of enzyme action 224

06 The mechanisms of enzyme action 225

0 J The general physical factors affecting enzyme action 227

0O Enzyme kinetics . 2286.8.1 Single substrate reactions 2286.8.2 Multiple substrate reactions 230

6.8.2.1 The sequential or single-displacement reactions 2306.8.2.2 Double-displacement or ping-pong reactions 231

»9 Enzyme inhibitors 2316.9.1 Reversible inhibitors 232

6.9.1.1 Competitive inhibition 2326.9.1.2 Non-competitive inhibition 2346.9.1.3 Uncompetitive inhibition 235

6.9.2 Irreversible inhibition 2366.9.2.1 Active site-directed inhibitors 2366.9.2.2 Suicide inhibitors 238

6.10 Transition state inhibitors 239

xii 1 Contents

6 . 1 1 Enzymes and drug design: some general considerations 242

6 . 1 2 Examples of drugs used as enzyme inhibitors 2436.12.1 Sulphonamides 2436.12.2 Captopril and its derivatives 245

O o l 3 Enzymes and drug resistance 2476.13.1 Changes in enzyme concentration 2486.13.2 An increase in the production of the substrate 2496.13.3 Changes in the structure of the enzyme 2506.13.4 The use of an alternative metabolic pathway 250

6 0 1 4 Ribozymes 250

6 O 1 § Summary 250

Questions 253

Complexes and chelating agents 255

Introduction 255

The shapes and structures of complexes 2577.2.1 Ligands z 258

7.2.1.1 The number of atoms forming bonds with the metal atom 2587.2.1.2 The number of electrons donated to the metal atom 2597.2.1.3 The type of bond formed with the metal atom 259

Simple ligands 2607i-Acceptor ligands 260

7.2.2 Bridging ligands 2627.2.3 Metal-metal bonds 2627.2.4 Metal clusters 263

Stability 2647.3.1 Stability and equilibrium constants 2647.3.2 Hard and soft acids and bases (HASB) 2667.3.3 Medical significance of stability 267

The general roles of metal complexes in biological processes 2677.4.1 Storage ' 2687.4.2 Transport 269

Contents

7.4.3 Detoxification 2727.4.4 Electron transfer 2737.4.5 Metalloenzymes 2737.4.6 Interaction with nucleic acids 2747.4.7 Structural role 275

Therapeutic uses 2767.5.1 Metal poisoning 2767.5.2 Anticancer agents 2797.5.3 Antiarthritics 281

Drug action and metal chelation 282

Summary 283

Questions 284

Receptors and messengers 287d introduction 287

. 2 The bonding of ligands to receptors 288

. 3 Structure and classification of receptors 291

«4 General mode of operation 2938.4.1 Superfamily type 1 2978.4.2 Superfamily type 2 2988.4.3 Superfamily type 3 3008.4.4 Superfamily type 4 302

§ Ligand-response relationships 3038.5.1 Experimental concentration-response curves 3048.5.2 Agonist concentration-response relationships 3058.5.3 Antagonist concentration-response relationships 3068.5.4 Partial agonists 3108.5.5 Desensitisation 310

6 Ligand-receptor theories 3118.6.1 Clark's occupancy theory j 3118.6.2 The rate theory ' 3168.6.3 The two-state model 317

Contents

Drug action and design 3188.7.1 Agonists 3188.7.2 Antagonists 321

Summary 321

Questions 325

Drug metabolism 327

Introduction 3279.1.1 Phase I and Phase II metabolic reactions 3279.1.2 The stereochemistry of drug metabolism 3299.1.3 Biological factors affecting metabolism 3309.1.4 Environmental factors affecting metabolism 3339.1.5 Species and metabolism 333

. 2 Secondary pharmacological implications of metabolism 3339.2.1 Inactive metabolites 3349.2.2 Metabolites with a similar activity to the drug 3349.2.3 Metabolites with a dissimilar activity to the drug 3349.2.4 Toxic metabolites 335

. 3 Sites of action / 335

. 4 Phase I metabolic reactions 3369.4.1 Oxidation 3379.4.2 Reduction 3389.4.3 Hydrolysis 339

. 5 Examples of Phase I metabolic reactions 3409.5.1 Alkanes 3409.5.2 Alkenes 3419.5.3 Alkynes 3429.5.4 Aromatic C-H 3429.5.5 Heterocyclic rings 3439.5.6 Alkyl halides 3449.5.7 Aryl halides 3469.5.8 Alcohols J 3469.5.9 Amines . 3469.5.10 Amides 348

Contents

9.5.119.5.129.5.139.5.149.5.159.5.169.5.179.5.189.5.199.5.20

Phase9.6.19.6.29.6.39.6.49.6.59.6.6

Aldehydes and ketonesCarboxylic acidsEpoxidesEthersEstersHydrazinesNitrilesNitroSulphides and sulphoxidesThiols

II metabolic routesAcylationSulphate formationConjugation with amino acidsConjugation with glucuronic acidConjugation with glutathioneMethylation

Pharmacokinetics of metabolites

Drug metabolism and drug design

Prodrugs9.9.1 Bioprecursor prodrugs9.9.2 Carrier prodrugs9.9.3 The design of prodrug systems for specific purposes

9.9.3.1 Improving absorption9.9.3.2 Improving patient acceptance9.9.3.3 Slow release9.9.3.4 Site specificity9.9.3.5 Minimising side effects

, 1 0 Summary

o i l Questions

Nucleic acidsIntroduction

xvi j Contents

Deoxyribonucleic acids (DNA) 376

10.2.1 Structure 376

The general functions of DNA 378

Genes 379

Replication 380

Ribonucleic adds (RNA) 381

Messenger RNA (mRNA) 382

Transfer RNA (tRNA) 384

Ribosomal RNA (rRNA) 385

Protein synthesis 38510.10.1 Activation 38610.10.2 Initiation 38710.10.3 Elongation 38710.10.4 Termination 389Protein synthesis in prokaryotic and eukaryotic cells 38910.11.1 Prokaryotic cells . 38910.11.2 Eukaryotic cells 391

)=12 Bacterial protein synthesis inhibitors (antimicrobials) 39210.12.1 Aminoglycosides 39310.12.2 Chloramphenicol 39510.12.3 Tetracyclines 396

Do 1 3 Drugs that target nucleic acids 39910.13.1 Antimetabolites 400

10.13.1.1 Antifolates 40110.13.1.2 Purine antimetabolites 40210.13.1.3 Pyrimidine antimetabolites 403

10.13.2 Enzyme inhibitors 40410.13.2.1 Topoisomerases 40410.13.2.2 Enzyme inhibitors for purine and pyrimidine precursor systems 404

10.13.3 Intercalating agents 40510.13.4 Alkylating agents 406

Contents

10.13.5 Antisense drugs10.13.6 Chain-cleaving agents

IO0I4 Viruses10.14.1 Structure10.14.2 Replication

10.14.2.1 RNA-viruses10.14.2.2 RNA-retroviruses10.14.2.3 DNA-viruses

10.14.3 Viral diseases10.14.4 Antiviral drugs

10.14.4.1 Nucleic acid synthesis inhibitorsAcyclovirVidarabineTribavirin (ribavirin)ZidovudineDidanosine

10.14.4.2 Host cell penetration inhibitorsAmantadine hydrochlorideRimantadine hydrochlorideInhibitors of Viral Protein Synthesis

10.14.4.3 Inhibitors of viral protein synthesis

1 0 . 1 5 Recombinant DNA (genetic engineering)10.15.1 Gene cloning10.15.2 Medical applications /

10.15.2.1 Gene therapy10.15.2.2 Manufacture of Pharmaceuticals

10.16 Summary

10.17 Questions

Nitric oxide 431

1 1 . 1 Introduction 431

1 1 . 2 The structure of nitric oxide 431

1 1 « 3 The chemical properties of nitric oxide 43211.3.1 Free radical reactions 432

Contents

11.3.1.1 Reaction with oxygen (oxidation)11.3.1.2 Reaction with superoxide (oxidation)

11.3.2 Salt formation11.3.2.1 Nitrosonium salts11.3.2.2 Nitroxyl ion (NO")

11.3.3 Reaction as an electrophile11.3.4 Reaction as an oxidising agent11.3.5 Complex formation

11.3.5.1 By direct reaction with nitric oxide11.3.5.2 By substitution of another ligand11.3.5.3 By substitution or addition of the nitrosonium ion11.3.5.4 Structural features of nitric oxide complexes

11.3.6 Nitric oxide complexes with iron11.3.6.1 Nitric oxide-iron-protein complexes11.3.6.2 Nitric oxide-iron-haem-protein complexes

11.3.7 The chemical properties of nitric oxide complexes11.3.7.1 Electrophilic behaviour11.3.7.2 Nucleophilic behaviour11.3.7.3 Oxidation of the nitric oxide ligand11.3.7.4 Exchange reactions

11.3.8 Reaction of nitric oxide with complexes11.3.8.1 Displacement reactions11.3.8.2 Other reactions

11.3.9 The chemistry of related compounds11.3.9.1 Nitrogen dioxide11.3.9.2 Dinitrogen trioxide (N2O3-)11.3.9.3 Nitrite11.9.3.4 Peroxynitrite

The cellular production and role of nitric oxide11.4.1 General mode of action11.4.2 Suitability of nitric oxide as a chemical messenger11.4.3 Metabolism

The role of nitric oxide in physiological andpathophysiological states11.5.1 The role of nitric oxide in the cardiovascular system11.5.2 The role of nitric oxide in the nervous system11.5.3 Nitric oxide and diabetes11.5.4 Nitric oxide and impotence11.5.5 Nitric oxide and the immune system

433435436436436436437437438438438438439439440442442442443443443443444444445446447448

448450451452

452453454456456457

1 1 . 6 Therapeutic possibilities 458

Contents

11.6.1 Compounds that reduce nitric oxide generation11.6.2 Compounds that supply nitric oxide11.6.3 The genetic approach

11»7 Summary

11.8 Questions

1 2 An introduction to organic drug andanalogue synthesis

12 .1 Introduction

12.2 Some general considerations12.2.1 Starting materials12.2.2 Practical considerations12.2.3 The overall design12.2.4 The use of protecting groups

12.3 Asymmetry in syntheses12.3.1 The use of non-stereospecific reactions to produce stereospecific centres12.3.2 The use of stereospecific reactions to produce stereospecific centres12.3.3 General methods of asymmetric synthesis

12.3.3.1 Methods that depend on the use of a catalyst for theirstereoselectivity

(i) Methods using enzymes as catalysts(ii) Methods using non-enzyme catalysts

12.3.3.2 Methods that do not use catalysts to produce stereoselectivity(i) Using chiral building blocks(ii) Using a chiral auxiliary(iii) Using achiral substrates and reagents

12.4 Designing organic syntheses 48212.4.1 An introduction to the disconnection approach 48212.4.2 Convergent synthesis 486

5 Partial organic synthesis of xenobiotics 491

12.6 Summary , 492

12.7 Questions 494

Contents

Selected further reading 495

Appendices 497

Appendix 1. Regression analysis 497

Appendix 2. Antibiotics 498

Appendix 3. Svedberg units (S) 498

Appendix 4. Cancer 499

Appendix 5. AIDS 499

Appendix 6. Sickel-cell anaemia 499

Answers to questions 501

Index 517