Contents

Part 1: Pharmacological Profiling: The Early Assessment of Pharmacological Properties 104

6.1 What Is Pharmacological Profiling? 104

6.2 Why Do Pharmacological Profiling? 105

6.2.1 The Regulatory Drive for Safe Medicines 105

6.2.2 Benefit to Drug Discovery and Development 105

6.3 Methods Applied to Pharmacological Profiling 107

6.3.1 Radioligand-Binding Assays 107

6.3.2 Functional In Vitro Assays 108

6.3.3 In Vivo Pharmacology Studies 109

6.4 Strategy for Pharmacological Profiling 109

6.5 Impact of Pharmacological Profiling 111

6.6 Predicting Functional Responses In Vivo from In Vitro Data 112

6.7 Maximizing the Strategy: Generation of Databases 114

6.8 In Silico Pharmacological Profiling 115

6.9 Concluding Remarks 116

Part 2: Strategic and Technical Aspects of Drug Profiling 116

6.10 Introduction 116

6.11 Pharmacological Profiling as the Tool to Avoid Drug Failure 117

6.11.1 Economic Environment: The Cost of Drug Failure 117

6.11.2 Understanding the Causes of Drug Failures 117

6.11.3 Predicting Side Effects to Prevent Drug Failures 118

6.11.3.1 Role of Pharmacological Profiling 118

6.11.3.2 Design of Pharmacological Profiles 118

6.11.3.3 Methods 121

6.11.3.3.1 Quality, Turnaround Time, and Cost 121

6.11.3.3.2 Binding vs. Functional Assays 125

6.12 Predicting Bioavailability: Pharmaceutical Profiling to Assess Absorption, Distribution, Metabolism, and Excretion Properties 125

6.13 Position of Profiling in Current Drug Discovery Process: When Profiling

Should Be Performed 129

Part 1 is written by Joanne Bowes, Michael G. Rolf, and Jean-Pierre Valentin from AstraZeneca R&D Alderley Park, U.K. and Part 2 by Valérie Hamon, Mark Crawford, and Thierry Jean from Cerep, U.S.A.

6.13.1 The Sequential vs. the Parallel Approach 129

6.13.2 The Reverse Sequential Approach Profiling before Screening 130

6.14 Conclusion 131

Acknowledgments 132

References 132

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