Medicinal Chemistry

Dr Gareth Thomas, The University of Portsmouth, UK.

"The many strengths of this introductory text include its seamless integration of biochemistry and pharmacology to direct drug discovery." (Journal of Medicinal Chemistry, September 2008)

• Preface to the First Edition xvPreface to the Second Edition xviiAcknowledgements xixAbbreviations xxi1 An introduction to drugs, their action and discovery 11.1 Introduction 11.2 What are drugs and why do we need new ones? 11.3 Drug discovery and design: a historical outline 31.3.1 The general stages in modern-day drug discovery and design 71.4 Leads and analogues: some desirable properties 91.4.1 Bioavailability 91.4.2 Solubility 101.4.3 Structure 101.4.4 Stability 111.5 Sources of leads and drugs 141.5.1 Ethnopharmaceutical sources 151.5.2 Plant sources 151.5.3 Marine sources 171.5.4 Microorganisms 181.5.5 Animal sources 201.5.6 Compound collections, data bases and synthesis 201.5.7 The pathology of the diseased state 211.5.8 Market forces and ‘me-too drugs’ 211.6 Methods and routes of administration: the pharmaceutical phase 211.7 Introduction to drug action 241.7.1 The pharmacokinetic phase (ADME) 251.7.2 The pharmacodynamic phase 321.8 Classification of drugs 331.8.1 Chemical structure 331.8.2 Pharmacological action 341.8.3 Physiological classification 341.8.4 Prodrugs 351.9 Questions 352 Drug structure and solubility 372.1 Introduction 372.2 Structure372.3 Stereochemistry and drug design 382.3.1 Structurally rigid groups 382.3.2 Conformation 392.3.3 Configuration 412.4 Solubility 442.4.1 Solubility and the physical nature of the solute 442.5 Solutions 462.6 The importance of water solubility 472.7 Solubility and the structure of the solute 492.8 Salt formation 502.9 The incorporation of water solubilising groups in a structure 522.9.1 The type of group 522.9.2 Reversible and irreversible groups 532.9.3 The position of the water solubilising group 532.9.4 Methods of introduction 542.9.5 Improving lipid solubility 592.10 Formulation methods of improving water solubility 592.10.1 Cosolvents 592.10.2 Colloidal solutions 592.10.3 Emulsions 602.11 The effect of pH on the solubility of acidic and basic drugs 612.12 Partition 632.12.1 Practical determination of partition coefficients 652.12.2 Theoretical determination of partition coefficients 662.13 Surfactants and amphiphiles 662.13.1 Drug solubilisation 692.13.2 Mixed micelles as drug delivery systems 712.13.3 Vesicles and liposomes 722.14 Questions 723 Structure–activity and quantitative structure relationships 753.1 Introduction 753.2 Structure–activity relationship (SAR) 763.3 Changing size and shape 773.3.1 Changing the number of methylene groups in chains and rings 773.3.2 Changing the degree of unsaturation 783.3.3 Introduction or removal of a ring system 783.4 Introduction of new substituents 803.4.1 Methyl groups 813.4.2 Halogen groups 833.4.3 Hydroxy groups 843.4.4 Basic groups 843.4.5 Carboxylic and sulphonic acid groups 853.4.6 Thiols, sulphides and other sulphur groups 853.5 Changing the existing substituents of a lead 863.6 Case study: a SAR investigation to discover potent geminal bisphosphonates 873.7 Quantitative structure–activity relationship (QSAR) 903.7.1 Regression analysis 933.7.2 The lipophilic parameters 943.7.3 Electronic parameters 993.7.4 Steric parameters 1023.8 Questions 1104 Computer-aided drug design 1134.1 Introduction 1134.1.1 Models 1144.1.2 Molecular modelling methods 1154.1.3 Computer graphics 1164.2 Molecular mechanics 1174.2.1 Creating a molecular model using molecular mechanics 1204.3 Molecular dynamics 1234.3.1 Conformational analysis 1244.4 Quantum mechanics 1244.5 Docking 1274.5.1 De novo design 1284.6 Comparing three-dimensional structures by the use of overlays 1304.6.1 An example of the use of overlays 1324.7 Pharmacophores and some of their uses 1334.7.1 High-resolution X-ray crystallography or NMR 1334.7.2 Analysis of the structures of different ligands 1344.8 Modelling protein structures 1354.9 Three-dimensional QSAR 1364.9.1 Advantages and disadvantages 1404.10 Other uses of computers in drug discovery 1414.11 Questions 1435 Combinatorial chemistry 1455.1 Introduction 1455.1.1 The design of combinatorial syntheses 1475.1.2 The general techniques used in combinatorial synthesis 1485.2 The solid support method 1485.2.1 General methods in solid support combinatorial chemistry 1505.2.2 Parallel synthesis 1525.2.3 Furka’s mix and split technique 1555.3 Encoding methods 1575.3.1 Sequential chemical tagging 1575.3.2 Still’s binary code tag system 1605.3.3 Computerised tagging 1615.4 Combinatorial synthesis in solution 1615.4.1 Parallel synthesis in solution 1625.4.2 The formation of libraries of mixtures 1635.4.3 Libraries formed using monomethyl polyethylene glycol (OMe-PEG) 1645.4.4 Libraries produced using dendrimers as soluble supports 1645.4.5 Libraries formed using fluorocarbon reagents 1655.4.6 Libraries produced using resin-bound scavenging agents 1665.4.7 Libraries produced using resin-bound reagents 1685.4.8 Resin capture of products 1685.5 Deconvolution 1695.6 High-throughput screening (HTS) 1705.6.1 Biochemical assays 1715.6.2 Whole cell assays 1735.6.3 Hits and hit rates 1735.7 Automatic methods of library generation and analysis 1745.8 Questions 1756 Drugs from natural sources 1776.1 Introduction 1776.2 Bioassays 1796.2.1 Screening tests 1806.2.2 Monitoring tests 1836.3 Dereplication 1856.4 Structural analysis of the isolated substance 1866.5 Active compound development 1886.6 Extraction procedures 1896.6.1 General considerations 1906.6.2 Commonly used methods of extraction 1916.6.3 Cleaning up procedures 1956.7 Fractionation methods 1956.7.1 Liquid–liquid partition 1966.7.2 Chromatographic methods 1996.7.3 Precipitation 2006.7.4 Distillation 2006.7.5 Dialysis 2026.7.6 Electrophoresis 2026.8 Case history: the story of Taxol 2026.9 Questions 2067 Biological membranes 2077.1 Introduction 2077.2 The plasma membrane 2087.2.1 Lipid components 2097.2.2 Protein components 2117.2.3 The carbohydrate component 2137.2.4 Similarities and differences between plasma membranes in different cells 2137.2.5 Cell walls 2147.2.6 Bacterial cell exterior surfaces 2177.2.7 Animal cell exterior surfaces 2187.2.8 Virus 2187.2.9 Tissue 2197.2.10 Human skin 2197.3 The transfer of species through cell membranes 2207.3.1 Osmosis 2207.3.2 Filtration 2217.3.3 Passive diffusion 2217.3.4 Facilitated diffusion 2237.3.5 Active transport 2237.3.6 Endocytosis 2247.3.7 Exocytosis 2257.4 Drug action that affects the structure of cell membranes and walls 2257.4.1 Antifungal agents 2267.4.2 Antibacterial agents (antibiotics) 2307.4.3 Local anaesthetics 2447.5 Questions 2498 Receptors and messengers 2518.1 Introduction 2518.2 The chemical nature of the binding of ligands to receptors 2528.3 Structure and classification of receptors 2548.4 General mode of operation 2568.4.1 Superfamily Type 1 2598.4.2 Superfamily Type 2 2608.4.3 Superfamily Type 3 2638.4.4 Superfamily Type 4 2648.5 Ligand–response relationships 2658.5.1 Experimental determination of ligand concentration–response curves 2668.5.2 Agonist concentration–response relationships 2678.5.3 Antagonist concentration–receptor relationships 2688.5.4 Partial agonists 2718.5.5 Desensitisation 2728.6 Ligand–receptor theories 2728.6.1 Clark’s occupancy theory 2728.6.2 The rate theory 2778.6.3 The two-state model 2788.7 Drug action and design 2798.7.1 Agonists 2798.7.2 Antagonists 2818.7.3 Citalopram, an antagonist antidepressant discovered by a rational approach 2828.7.4 b-Blockers 2858.8 Questions 2899 Enzymes 2919.1 Introduction 2919.2 Classification and nomenclature 2939.3 Active sites and catalytic action 2959.3.1 Allosteric activation 2979.4 Regulation of enzyme activity 2989.4.1 Covalent modification 2989.4.2 Allosteric control 2989.4.3 Proenzyme control 3009.5 The specific nature of enzyme action 3009.6 The mechanisms of enzyme action 3029.7 The general physical factors affecting enzyme action 3029.8 Enzyme kinetics 3039.8.1 Single substrate reactions 3039.8.2 Multiple substrate reactions 3059.9 Enzyme inhibitors 3069.9.1 Reversible inhibitors 3079.9.2 Irreversible inhibition 3129.10 Transition state inhibitors 3189.11 Enzymes and drug design: some general considerations 3209.12 Examples of drugs used as enzyme inhibitors 3219.12.1 Sulphonamides 3219.12.2 Captopril and related drugs 3239.12.3 Statins 3269.13 Enzymes and drug resistance 3299.13.1 Changes in enzyme concentration 3309.13.2 An increase in the production of the substrate 3319.13.3 Changes in the structure of the enzyme 3319.13.4 The use of an alternative metabolic pathway 3329.14 Ribozymes 3329.15 Questions 33210 Nucleic acids 33510.1 Introduction 33510.2 Deoxyribonucleic acid (DNA) 33610.2.1 Structure 33710.3 The general functions of DNA 33810.4 Genes 33910.5 Replication 34010.6 Ribonucleic acid (RNA) 34110.7 Messenger RNA (mRNA) 34210.8 Transfer RNA (tRNA) 34310.9 Ribosomal RNA (rRNA) 34510.10 Protein synthesis 34510.10.1 Activation 34510.10.2 Initiation 34610.10.3 Elongation 34710.10.4 Termination 34810.11 Protein synthesis in prokaryotic and eukaryotic cells 34810.11.1 Prokaryotic cells 34810.11.2 Eukaryotic cells 35010.12 Bacterial protein synthesis inhibitors (antimicrobials) 35010.12.1 Aminoglycosides 35110.12.2 Chloramphenicol 35510.12.3 Tetracyclines 35610.12.4 Macrolides 35910.12.5 Lincomycins 36010.13 Drugs that target nucleic acids 36210.13.1 Antimetabolites 36210.13.2 Enzyme inhibitors 36810.13.3 Intercalating agents 37210.13.4 Alkylating agents 37410.13.5 Antisense drugs 37710.13.6 Chain cleaving agents 37910.14 Viruses 38010.14.1 Structure and replication 38010.14.2 Classification 38110.14.3 Viral diseases 38310.14.4 Antiviral drugs 38410.15 Recombinant DNA technology (genetic engineering) 38910.15.1 Gene cloning 38910.15.2 Medical applications 39210.16 Questions 40111 Pharmacokinetics 40311.1 Introduction 40311.1.1 General classification of pharmacokinetic properties 40511.1.2 Drug regimens 40511.1.3 The importance of pharmacokinetics in drug discovery 40611.2 Drug concentration analysis and its therapeutic significance 40711.3 Pharmacokinetic models 40911.4 Intravascular administration 41111.4.1 Distribution 41211.5 Extravascular administration 42511.5.1 Dissolution 42811.5.2 Absorption 42911.5.3 Single oral dose 43011.5.4 The calculation of tmax and Cmax 43311.5.5 Repeated oral doses 43411.6 The use of pharmacokinetics in drug design 43511.7 Extrapolation of animal experiments to humans 43511.8 Questions 43612 Drug metabolism 43912.1 Introduction 43912.1.1 The stereochemistry of drug metabolism 43912.1.2 Biological factors affecting metabolism 44012.1.3 Environmental factors affecting metabolism 44312.1.4 Species and metabolism 44312.1.5 Enzymes and metabolism 44312.2 Secondary pharmacological implications of metabolism 44312.2.1 Inactive metabolites 44412.2.2 Metabolites with a similar activity to the drug 44412.2.3 Metabolites with a dissimilar activity to the drug 44412.2.4 Toxic metabolites 44512.3 Sites of action 44512.4 Phase I metabolic reactions 44612.4.1 Oxidation 44612.4.2 Reduction 44812.4.3 Hydrolysis 44812.4.4 Hydration 44912.4.5 Other Phase I reactions 44912.5 Examples of Phase I metabolic reactions 44912.6 Phase II metabolic routes 45412.7 Pharmacokinetics of metabolites 45712.8 Drug metabolism and drug design 45812.9 Prodrugs 46012.9.1 Bioprecursor prodrugs 46112.9.2 Carrier prodrugs 46212.9.3 Photoactivated prodrugs 46412.9.4 The design of carrier prodrug systems for specific purposes 46512.10 Questions 47513 Complexes and chelating agents 47713.1 Introduction 47713.2 The shapes and structures of complexes 47813.2.1 Ligands 47913.2.2 Bridging ligands 48313.2.3 Metal–metal bonds 48313.2.4 Metal clusters 48313.3 Metal–ligand affinities 48513.3.1 Affinity and equilibrium constants 48513.3.2 Hard and soft acids and bases 48713.3.3 The general medical significance of complex stability 48813.4 The general roles of metal complexes in biological processes 48813.5 Therapeutic uses 49113.5.1 Metal poisoning 49113.5.2 Anticancer agents 49413.5.3 Antiarthritics 49713.5.4 Antimicrobial complexes 49813.5.5 Photoactivated metal complexes 49913.6 Drug action and metal chelation 50113.7 Questions 50114 Nitric oxide 50314.1 Introduction 50314.2 The structure of nitric oxide 50314.3 The chemical properties of nitric oxide 50414.3.1 Oxidation 50514.3.2 Salt formation 50614.3.3 Reaction as an electrophile 50714.3.4 Reaction as an oxidising agent 50714.3.5 Complex formation 50814.3.6 Nitric oxide complexes with iron 50814.3.7 The chemical properties of nitric oxide complexes 51014.3.8 The chemistry of related compounds 51214.4 The cellular production and role of nitric oxide 51414.4.1 General mode of action 51614.4.2 Suitability of nitric oxide as a chemical messenger 51814.4.3 Metabolism 51814.5 The role of nitric oxide in physiological and pathophysiological states 51914.5.1 The role of nitric oxide in the cardiovascular system 51914.5.2 The role of nitric oxide in the nervous system 52014.5.3 Nitric oxide and diabetes 52214.5.4 Nitric oxide and impotence 52214.5.5 Nitric oxide and the immune system 52314.6 Therapeutic possibilities 52414.6.1 Compounds that reduce nitric oxide generation 52414.6.2 Compounds that supply nitric oxide 52614.6.3 The genetic approach 52914.7 Questions 52915 An introduction to drug and analogue synthesis 53115.1 Introduction 53115.2 Some general considerations 53215.2.1 Starting materials 53215.2.2 Practical considerations 53215.2.3 The overall design 53215.2.4 The use of protecting groups 53315.3 Asymmetry in syntheses 53415.3.1 The use of non-stereoselective reactions to produce stereospecific centres 53515.3.2 The use of stereoselective reactions to produce stereogenetic centres 53515.3.3 General methods of asymmetric synthesis 54115.3.4 Methods of assessing the purity of stereoisomers 54715.4 Designing organic syntheses 54815.4.1 An introduction to the disconnection approach 54815.4.2 Convergent synthesis 55415.5 Partial organic synthesis of xenobiotics 55615.6 Questions 55716 Drug development and production 55916.1 Introduction 55916.2 Chemical development 56016.2.1 Chemical engineering issues 56116.2.2 Chemical plant: health and safety considerations 56216.2.3 Synthesis quality control 56316.2.4 A case study 56316.3 Pharmacological and toxicological testing 56516.4 Drug metabolism and pharmacokinetics 56916.5 Formulation development 57016.6 Production and quality control 57016.7 Patent protection 57116.8 Regulation 57216.9 Questions 573Selected further reading 575Answers to questions 579Index 601