Medicinal Chemistry

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