Preface XIII

List of Contributors XVII

Part I General Aspects 1

1 Serendipitous Target-Based Drug Discoveries 3
János Fischer and David P. Rotella

1.1 Introduction 3

1.2 Recent Examples of Target-Based Drug Discovery 4

1.3 Serendipitous Target-Based Drug Discoveries 7

1.4 Drospirenone (Contraceptive with Anti-aldosterone Activity) 7

1.4.1 Summary of Drospirenone Discovery 8

1.5 Escitalopram (Selective Serotonin Reuptake Inhibitor Antidepressant) 9

1.5.1 Summary of the Escitalopram Discovery 11

1.6 Ezetimibe (Inhibitor of Cholesterol Absorption) 11

1.6.1 Summary of Ezetimibe Discovery 13

1.7 Lamotrigine (Discovery of a Standalone Drug for the Treatment of Epilepsy) 13

1.7.1 Summary of Lamotrigine Discovery 15

1.8 Omeprazole (Proton Pump Inhibitor Acid-Suppressive Agent) 15

1.8.1 Summary of Omeprazole Discovery 16

1.9 Outlook 17

Acknowledgments 17

List of Abbreviations 17

References 18

2 Drug Discoveries and Molecular Mechanism of Action 19
David C. Swinney

2.1 Introduction 19

2.2 Mechanistic Paradox 19

2.3 Molecular Mechanism of Action 20

2.3.1 The Primary Driver of an Optimal MMOA is the Potential for Mechanism-Based Toxicity 22

2.3.2 Details of MMOA are not Captured by IC50 and KI 22

2.3.3 Metrics, Biochemical Efficiency 24

2.4 How MMOAs were Discovered 25

2.4.1 MMOAs of Medicines Approved by the USFDA Between 1999 and 2008 27

2.5 Case Study: Artemisinin 30

2.6 Summary 31

List of Abbreviations 32

References 32

Part II Drug Class 35

3 Insulin Analogs – Improving the Therapy of Diabetes 37
John M. Beals

3.1 Introduction 37

3.2 Pharmacology and Insulin Analogs 38

3.3 Chemical Description 39

3.4 Rapid-Acting Insulin Analogs (Prandial or Bolus Insulin) 41

3.5 Long-Acting Insulin Analog Formulations (Basal Insulin) 48

3.6 Conclusions and Future Considerations 54

List of Abbreviations 55

References 55

Part III Case Histories 61

4 The Discovery of Stendra™(Avanafil) for the Treatment of Erectile Dysfunction 63
Koichiro Yamada, Toshiaki Sakamoto, Kenji Omori, and Kohei Kikkawa

4.1 Introduction 63

4.2 Discovery of Avanafil 65

4.2.1 Differentiation Strategies to Develop a New Drug 65

4.2.2 Discovery of Isoquinoline Derivatives from Isoquinolinone Lead 65

4.2.3 Scaffold-Hopping Approaches from the Isoquinoline Leads 67

4.2.3.1 Monocyclic Type A Series: Tetrasubstituted Pyrimidine Derivatives 68

4.2.3.2 Monocyclic Type B Series: Trisubstituted Pyrimidine Derivatives 68

4.2.3.3 SAR of Substitution at the 2-Position of the Pyrimidine Ring (15) 70

4.2.3.4 SAR of Substitution at the 4-Position of the Pyrimidine Ring (16) 70

4.2.3.5 SAR of Substitution at the 5-Position of the Pyrimidine Ring (19, 20) 73

4.2.3.6 Core Structure Modifications of the Pyrimidine Nucleus of Avanafil 73

4.3 Pharmacological Features of Avanafil 75

4.3.1 PDE Inhibitory Profiles 75

4.3.2 In Vivo Pharmacology 76

4.3.2.1 Potentiation of Penile Tumescence in Dogs 76

4.3.2.2 Influence on Retinal Function in Dogs 79

4.3.2.3 Influence on Hemodynamics in Dogs 79

4.3.2.4 Influence on Nitroglycerin (NTG)-Induced Hypotension in Dogs 80

4.4 Clinical Studies of Avanafil 81

4.5 Conclusion 83

List of Abbreviations 83

References 83

5 Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes 87
William N.Washburn

5.1 Introduction 87

5.2 Role of SGLT2 Transporters in Renal Function 88

5.3 O-Glucoside SGLT2 Inhibitors 89

5.3.1 Hydroxybenzamide O-Glucosides 90

5.3.2 Benzylpyrazolone O-Glucosides 94

5.3.3 o-Benzylphenol O-Glucosides 95

5.4 m-Diarylmethane C-Glucosides 97

5.4.1 Synthetic Route 98

5.4.2 Early SAR of C-Glucoside Based SGLT2 Inhibitors 99

5.4.3 Identification of Dapagliflozin 102

5.5 Profiling Studies with Dapagliflozin 105

5.6 Clinical Studies with Dapagliflozin 108

5.7 Summary 108

List of Abbreviations 109

References 110

6 Elvitegravir, A New HIV-1 Integrase Inhibitor for Antiretroviral Therapy 113
Hisashi Shinkai

6.1 Introduction 113

6.2 Discovery of Elvitegravir 114

6.2.1 HIV-1 Integrase and Diketo Acid Inhibitors 114

6.2.2 Monoketo Acid Integrase Inhibitors and Elvitegravir 116

6.3 Conclusion 121

List of Abbreviations 123

References 123

7 Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus 129
Matthias Eckhardt, Thomas Klein, Herbert Nar, and Sandra Thiemann

7.1 Introduction 129

7.2 Discovery of Linagliptin – HighThroughput Screening Hit Optimization 130

7.3 Rationalization of DPP-4 Inhibition Potency by Crystal Structure Analysis and Studies of Binding Kinetics 139

7.4 Basic Physicochemical, Pharmacological, and Kinetic Characteristics 141

7.5 Preclinical Studies 143

7.5.1 Glucose Regulation by Linagliptin 143

7.5.2 Effects of Linagliptin on the Kidney 145

7.6 Clinical Studies 146

7.6.1 Clinical Pharmacokinetics 146

7.6.2 Clinical Pharmacodynamics 148

7.6.2.1 Inhibition of DPP-4 148

7.6.2.2 Effects on Glucagon-Like Peptide-1 and Hyperglycemia 148

7.6.3 Clinical Use in Special Patient Populations 148

7.6.3.1 Patients with Renal Impairment 148

7.6.3.2 Patients with Hepatic Impairment 150

7.6.4 Cardiovascular Safety 150

7.7 Conclusion 151

List of Abbreviations 151

References 152

8 The Discovery of Alimta (Pemetrexed) 157
Edward C. Taylor

List of Abbreviations 175

References 176

9 Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy 181
Shigeki Hibi

9.1 Introduction 181

9.1.1 Competitive Receptor Antagonists 182

9.1.2 Noncompetitive Receptor Antagonists 182

9.2 Seeds Identification by High Throughput Screening (HTS) Assays 183

9.3 Structure and Activity Relationship (SAR) Study Starting from the Unique Structure of Seed Compounds 184

9.3.1 Introduction of Conjugated Aromaticity 184

9.3.2 Discovery of 1,3,5-Triaryl-1H-pyridin-2-one Template 184

9.3.3 Optimization of 1,3,5-Triaryl-1H-pyridin-2-one Derivatives 185

9.4 Pharmacological Properties of Perampanel; Selection for Clinical Development 187

9.4.1 The Pharmacological Evaluation of Perampanel 187

9.4.2 The Pharmacokinetic Evaluation of Perampanel 189

9.5 Clinical Development of Perampanel 189

9.5.1 Phase I 189

9.5.2 Phase II and Phase III 190

9.6 Conclusion 190

List of Abbreviations 190

References 191

10 Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection 195
Bhisetti G. Rao, Mark A. Murcko, Mark J. Tebbe, and Ann D. Kwong

10.1 Introduction 195

10.1.1 Crystal Structure of NS3/4A Protease 196

10.1.2 Assays 196

10.2 Discussion 197

10.2.1 Substrate-Based Inhibitor Design 197

10.2.2 Structure-Based Inhibitor Optimization 200

10.2.3 Pre-Clinical Development 206

10.2.4 Clinical Development 206

10.3 Summary 207

List of Abbreviations 208

References 209

11 Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1) 213
Sandhya Girish, Gail D. Lewis Phillips, Fredric S. Jacobson, Jagath R. Junutula, and Ellie Guardino

11.1 Introduction 213

11.2 Molecular Design of T-DM1 214

11.3 Strategies for Bioanalysis 216

11.4 Strategies for Chemistry and Manufacturing Control 218

11.5 Nonclinical Development 219

11.6 Clinical Pharmacology 220

11.7 Clinical Trials and Approval 222

11.8 Summary 224

List of Abbreviations 225

References 226

Index 231

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