Medicinal Chemistry: Principles and Practice

Transcription

1 Medicinal Chemistry: Principles and Practice Edited by Frank D. King SmithKline Beecham Pharmaceuticals, Harlow, UK ^ THE ROYAL SOCIETY OF CHEMISTRY

2 Contents Chapter 1 An Introduction to Drug-Receptor Interactions Barry Hunt 1 Introduction 1 2 Drug Agonists: Dose-Response Relationships 4 3 Drug Antagonism 6 4 Partial Agonism 8 5 Relationship between Affinity and Efficacy Factors 9 6 Spare Receptors 10 7 Two State Theory 10 8 Binding Sites 12 9 Receptor Characterisation Transduction Linkages Receptor Constancy Conclusion Bibliography 18 Chapter 2 Signal Transduction and Second Messengers Trevor J. Franklin 1 Introduction 20

3 xii Contents 2 Second Messengers Cyclic AMP Activation of Adenylyl Cyclase Inhibition of Adenylyl Cyclase Heterogeneity of G-Proteins and Adenylyl Cyclases Intracellular Receptors for camp: camp-dependent Protein Kinases Termination of the camp Signalling Process Phosphodiesterases (PDEs) Phosphoprotein Phosphatases Desensitisation of the Receptor-G-Protein-Adenylyl Cyclase Complex to Agonist Stimulation 25 Cyclic Guanosine 3'-5'-Monophosphate (cgmp) 26 Guanylyl Cyclase 26 Intracellular Receptors for cgmp 26 Products of Phospholipid Metabolism as Second Messengers 27 Diacylglycerol (DAG) and Protein Kinase (PKC) 28 Inositol 1,4,5-Triphosphate and Intracellular Calcium 29 Ryanodine Receptors 30 Intracellular Receptors for Calcium 30 Termination of the IP 3 -DAG-Ca 2 + Signals 31 3 Signalling by Receptor Tyrosine Kinases 31 SH2 and SH3 Domains 32 4 Final Comments 34 5 Further Reading 35 Chapter 3 Enzyme Inhibitors David A. Roberts 1 Introduction 36 2 Enzyme Inhibitor Categories 38 Reversible Enzyme Inhibitors 39 Reversible Competitive Inhibition 40 Reversible Non-competitive Inhibition 42 Irreversible Enzyme Inhibitors 43 3 Options for Drug Design 45 4 Examples of Enzyme Inhibitors 47 Angiotensin Converting Enzyme and Renin Inhibitors 47 Hydroxymethylglutaryl-CoA Reductase (HMGCoA Reductase) Inhibitors 51

4 Contents xiii 5 Concluding Remarks 52 6 Acknowledgements 52 7 Additional Reading 52 Chapter 4 The Biological Evaluation of New Compounds Robert A. Coleman 1 Introduction 53 2 In Vitro Evaluation 54 Ligand Binding 54 Measurement of Second Messengers 56 Measurement of Functional Activity 56 Quantification of Agonist Activity 56 Tissue Immersion or Superfusion? 58 Tachyphylaxis 62 Quantification of Antagonist Activity 62 3 In Vivo Testing 63 Anaesthetised Animals 64 Conscious Animals 65 4 Conclusions 65 5 Bibliography 66 Chapter 5 Pharmacokinetics Robert M.J. Ings 1 Introduction 67 Definitions 67 The Pharmacokineticist in Industry 68 Physical Chemical Properties of Drugs and Their Pharmacokinetics 68 2 Absorption 70 Mechanism of Absorption 70 Incomplete Absorption 72 Biopharmaceutical Factors 74 Animal Models to Determine Absorption 74 3 Distribution 74 Factors Influencing Drug Distribution 74

5 xiv Contents 4 Elimination 76 Route of Elimination 76 Clearance 79 5 Conclusions 84 6 Bibliography 85 Chapter 6 Drug Metabolism Colin Vose 1 Introduction 86 2 Drug Metabolism Pathways 86 3 Sites of Drug Metabolism 89 4 Relationship between Structure and Extent of Metabolism 90 5 How is Drug Metabolism Studied? 91 6 Why Do We Study Drug Metabolism? 91 7 What Factors Can Modify Drug Metabolism? 93 Dose Level 93 Route of Administration 94 Species 95 Sex-related Differences 95 Age 96 Disease 96 Drug Interactions 96 Genetics 96 8 Conclusions 97 9 References Bibliography 97 Chapter 7 Physicochemical Properties and Drug Design Nigel P. Gensmantel 1 Introduction 98 2 Electronic Properties and Ionisation Constants 98

6 Contents xv 3 Hammett Relationship 99 4 Hydrophobic Interactions and Lipophilicity Partition Coefficient as an Index of Lipophilicity Ionisation and Its Effects on the Partition Coefficient Predicting Lipophilicity Steric Parameters Hydrogen Bonding Prediction of Drug-Receptor Interactions 109 Mutagenesis Studies. 109 Ligand Binding Studies 109 Statistically Derived Group Contributions Conclusions Acknowledgements References 111 Chapter 8 Quantitative Structure Activity Relationships Andrew M. Davis 1 Introduction SARVJ. QSAR? Linear Regression and Multiple Linear Regression Designing the Initial Synthetic Targets - Cluster Analysis Progressive Methods - Principal Components Analysis (PCA)/Principal Components Regression (PCR) Partial Least Squares (PLS) Analysis D QSAR Methods Conclusions References 129

7 xvi Contents Chapter 9 Considerations for the Use of Computational Chemistry Techniques by Medicinal Chemists Mike M. Hann 1 Introduction Energy Calculations Introduction Quantum Mechanics Molecular Mechanics Analysis of Conformational Space 3 Databases 4 De Novo Ligand Design 5 Molecular Graphics and the Visualisation of Molecules 6 Acknowledgements 7 References Chapter 10 'Patent Medicine' Bill Tyrrell 1 Introduction 2 Patents in the Wider Context of Intellectual Property 3 What is a Patent? 4 What Can Be Patented? 5 Requirements for Patentability Utility Novelty Inventive Step Sufficiency of Disclosure 6 Patent Restrictions Geographic Constraints Patent Term Scope of Claims 7 How Are Patents Obtained?

8 Contents xvii 8 The Power,of Patents Patents and Politics Conclusion Footnotes and References 163 Chapter 11 Molecular Biology - A New Route to Drug Discovery Janet E. Carey 1 DNA Structure What Determines the Differences between Cell Types? Gene Cloning - Propagation of Genetic Material in Alternative Host Systems Expression of Cloned Genes Uses of Cloned Human Proteins 172 Use of Proteins as Therapeutic Agents Exemplified by the Development of Novel Thromboly tics 172 Proteins as Screening Tools 175 Genetically Engineered Proteins as Structure/Function Mapping Tools References 178 Chapter 12 Devising a Research Strategy Colin W. Greengrass 1 Introduction Deciding on an Area for Research Screen Sequences Finding a Lead How Can the Quality of a Lead Be Assessed? Summary References 188

9 xviii Contents Chapter 13 Past Approaches to Discovering New Drugs as Medicines C. Robin Ganellin, FRS 1 Introduction Drugs Derived from Natural Products Existing Drugs as a Source for New Drug Discovery Using Disease Models as Screens for New Drug Leads Physiological Mechanisms: the Modern 'Rational Approach' to Drug Design Uncertainties in Designing Drugs to Become Medicines References 204 Chapter 14 Bioisosteres, Conformational Restriction and Pro-drugs: Approaches to Lead Optimisation - Case History: An Example of a Conformational Restriction Approach Frank D. King 1 Introduction Bioisosteric Replacement Conformational Restriction 209 Increase in Receptor/Enzyme Selectivity 210 Increase in Receptor/Enzyme Affinity 211 Definition of the'pharmacophore' 212 Metabolic Stabilisation 213 Reduced Intrinsic Activity of Agonists 213 Peptides: Mimicry of the Tertiary Structure of Proteins 214 Novel Structural Types Pro-drugs Case Historty: from Metoclopramide to Selective Dopamine, 5-HT 3, and 5-HT4 Receptor Antagonists and 5-HT 4 Receptor Agonists 218 Conformational Restriction of the Side Chain 219 Conformational Restriction of the Amide 223 Cyclisation of the ortho-alkoxy Group References 225

10 Contents xix Chapter 15 The Design and Synthesis of Selective Protein Kinase C Inhibitors Christopher H. Hill 1 Introduction In Pathological Processes Inhibitor Design Cellular and In Vivo Studies Chemistry Conclusion References 239 Chapter 16 Discovery of 1069C - A Novel Synthetic Antitumour Agent with Low Cross-Resistance Potential Simon T. Hodgson 1 Introduction Strategy for Discovery of Antitumour Microtubule Inhibitors Discovery of the Lead Compound Computer Modelling of 1069C and Natural Product; Ligands at the Colchicine Site SAR Studies (In Vitro) 247 Side-chain Aromatic Group 247 Carbamate Group 248 Investigation of the Linker Group: a Molecular Dynamics Approach 248 Working Model In Vitro Antitumour Activity Conclusions Acknowledgements References 254

11 xx Contents Chapter 17 The Design and Biological Properties of 'Dipeptoid' Antagonists David C. Horwell 1 Introduction Identification of the Dipeptide Chemical Lead Enhancement of the Boc-Trp-Phe-NH 2 Dipeptide Chemical Lead Developments of 'Dipeptoids' with Nanomolar Affinity for the CCK-B Receptor Conclusion Acknowledgements References 264 Chapter 18 Migraine Therapy from Serotonin to Sumatriptan Peter C. North 1 The Symptoms and Prevalence of Migraine Acute Therapy The Role of 5-Hydroxytryptamine in Migraine Selective 5-HT Agonists - a Novel Mechanism to Treat Migraine? The Pharmacology of Methysergide Project Objectives and Medicinal Chemical Strategy Early Milestones The Discovery of Sumatriptan Clinical Trial Results with Sumatriptan Conclusions Acknowledgements References 276

12 Contents xxi Chapter 19 Drug Development Jane Ormerod 1 Introduction Planning for Development Chemical Development Formulation Development Pharmacology Safety Evaluation Drug Metabolism and Pharmacokinetics Clinical References 289 Appendices 1. Summary of Receptor Properties Summary of Ion Channel Properties Enzyme Commission Classification of Enzymes Schematic Representations of Mechanisms of Proteases Table of Substituent Constants JC, MR, F, R,and a An Example of a Craig Diagram Plot of a vs. n Summary of Common Routes of Administration Approximate Conversion Factors for Alog to Ratio Conversion Factors for Solutions and Dosages: Molar vs. Weight 305 Subject Index 307