See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/240331371

Medicinal Chemistry: Principles and Practice

Book · January 1994

CITATIONS READS
47 6,557

1 author:

Frank D King
University College London
139 PUBLICATIONS   3,159 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

triflic acid mediated cyclisations View project

All content following this page was uploaded by Frank D King on 13 March 2014.

The user has requested enhancement of the downloaded file.

Medicinal Chemistry: Principles
and Practice

Edited by
Frank D. King
SmithKline Beecham Pharmaceuticals, Harlow, UK

THE ROYAL
SOCIETY OF
^ CHEMISTRY
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 13

10 Transduction Linkages 16

11 Receptor Constancy 18

12 Conclusion 18

13 Bibliography 18

Chapter 2 Signal Transduction and Second Messengers

Trevor J. Franklin

1 Introduction 20
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
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
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 97

10 Bibliography 97

Chapter 7 Physicochemical Properties and Drug Design

Nigel P. Gensmantel

1 Introduction 98

2 Electronic Properties and Ionisation Constants 98

Contents xv

3 Hammett Relationship 99

4 Hydrophobic Interactions and Lipophilicity 101

5 Partition Coefficient as an Index of Lipophilicity 102

6 Ionisation and Its Effects on the Partition Coefficient 102

7 Predicting Lipophilicity 104

8 Steric Parameters 106

9 Hydrogen Bonding 107

10 Prediction of Drug-Receptor Interactions 109

Mutagenesis Studies . 109
Ligand Binding Studies 109
Statistically Derived Group Contributions 110

11 Conclusions 111

12 Acknowledgements 111

13 References 111

Chapter 8 Quantitative Structure—Activity Relationships

Andrew M. Davis

1 Introduction 114

2 SARVJ. QSAR? 116

3 Linear Regression and Multiple Linear Regression 117

4 Designing the Initial Synthetic Targets - Cluster Analysis 121

5 Progressive Methods - Principal Components Analysis

(PCA)/Principal Components Regression (PCR) 123

6 Partial Least Squares (PLS) Analysis 125

7 3-D QSAR Methods 126

8 Conclusions 128

9 References 129
xvi Contents

Chapter 9 Considerations for the Use of Computational Chemistry

Techniques by Medicinal Chemists
Mike M. Hann

1 Introduction 130

2 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?

Contents xvii

8 The Power,of Patents 160

9 Patents and Politics 162

10 Conclusion 162

11 Footnotes and References 163

Chapter 11 Molecular Biology - A New Route to Drug Discovery

Janet E. Carey

1 DNA Structure 166

2 What Determines the Differences between Cell Types? 169

3 Gene Cloning - Propagation of Genetic Material in

Alternative Host Systems 170
4 Expression of Cloned Genes 171

5 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 176

6 References 178

Chapter 12 Devising a Research Strategy

Colin W. Greengrass

1 Introduction 179

2 Deciding on an Area for Research 179

3 Screen Sequences 181

4 Finding a Lead 182

5 How Can the Quality of a Lead Be Assessed? 186

6 Summary 188

7 References 188
xviii Contents

Chapter 13 Past Approaches to Discovering New Drugs as Medicines

C. Robin Ganellin, FRS

1 Introduction .. 189

2 Drugs Derived from Natural Products 189

3 Existing Drugs as a Source for New Drug Discovery 191

4 Using Disease Models as Screens for New Drug Leads 193

5 Physiological Mechanisms: the Modern 'Rational

Approach' to Drug Design 194

6 Uncertainties in Designing Drugs to Become Medicines 202

7 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 206

2 Bioisosteric Replacement 207

3 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 215

4 Pro-drugs 215

5 Case Historty: from Metoclopramide to Selective Dopamine,

5-HT3, and 5-HT4 Receptor Antagonists and 5-HT4
Receptor Agonists 218
Conformational Restriction of the Side Chain 219
Conformational Restriction of the Amide 223
Cyclisation of the ortho-Alkoxy Group 224

6 References 225
Contents xix

Chapter 15 The Design and Synthesis of Selective Protein Kinase C Inhibitors

Christopher H. Hill

1 Introduction 226

2 In Pathological Processes 227

3 Inhibitor Design 228

4 Cellular and In Vivo Studies 235

5 Chemistry 236

6 Conclusion 239

7 References 239

Chapter 16 Discovery of 1069C - A Novel Synthetic Antitumour Agent with

Low Cross-Resistance Potential
Simon T. Hodgson

1 Introduction 241

2 Strategy for Discovery of Antitumour Microtubule

Inhibitors 242

3 Discovery of the Lead Compound 243

4 Computer Modelling of 1069C and Natural Product;

Ligands at the Colchicine Site 245
5 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 250

6 In Vitro Antitumour Activity 251

7 Conclusions 252

8 Acknowledgements 253

9 References 254
xx Contents

Chapter 17 The Design and Biological Properties of 'Dipeptoid' Antagonists

David C. Horwell

1 Introduction 255

2 Identification of the Dipeptide Chemical Lead 257

3 Enhancement of the Boc-Trp-Phe-NH2 Dipeptide

Chemical Lead 258
4 Developments of 'Dipeptoids' with Nanomolar Affinity

for the CCK-B Receptor 260

5 Conclusion 263

6 Acknowledgements . 263

7 References 264

Chapter 18 Migraine Therapy — from Serotonin to Sumatriptan

Peter C. North

1 The Symptoms and Prevalence of Migraine 265

2 Acute Therapy 265

3 The Role of 5-Hydroxytryptamine in Migraine 266

4 Selective 5-HT Agonists - a Novel Mechanism to Treat

Migraine? 267

5 The Pharmacology of Methysergide 267

6 Project Objectives and Medicinal Chemical Strategy 269

7 Early Milestones 269

8 The Discovery of Sumatriptan 272

9 Clinical Trial Results with Sumatriptan 275

10 Conclusions 276
11 Acknowledgements 276
12 References 276
Contents xxi

Chapter 19 Drug Development

Jane Ormerod

1 Introduction 278

2 Planning for Development 279

3 Chemical Development 280

4 Formulation Development 282

5 Pharmacology 282

6 Safety Evaluation 283

7 Drug Metabolism and Pharmacokinetics 284

8 Clinical 285

9 References 289

Appendices

1. Summary of Receptor Properties 290

2. Summary of Ion Channel Properties 295

3. Enzyme Commission Classification of Enzymes 297

4. Schematic Representations of Mechanisms of Proteases 299

5. Table of Substituent Constants JC, MR, F, R ,and a. 301

6. An Example of a Craig Diagram Plot of a vs. n 303

7. Summary of Common Routes of Administration 304

8. Approximate Conversion Factors for Alog to Ratio 305

9. Conversion Factors for Solutions and Dosages: Molar vs.

Weight 305
Subject Index 307

View publication