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PREFACE xv CONTRIBUTORS xvii CHAPTER 1 INTRODUCTION: DRUG DISCOVERY IN DIFFICULT TIMES 1 Malcolm MacCoss CHAPTER 2 DISCOVERY AND DEVELOPMENT OF THE DPP–4 INHIBITOR JANUVIA??? (SITA–GLIPTIN) 10 Emma R. Parmee, Ranabir SinhaRoy, Feng Xu, Jeffrey C. Givand, and Lawrence A. Rosen 2.1 Introduction 10 2.2 DPP–4 Inhibition as a Therapy for Type 2 Diabetes: Identification of Key Determinants for Efficacy and Safety 10 2.3 Medicinal Chemistry Program 20 2.4 Synthetic and Manufacturing Routes to Sitagliptin 27 2.5 Drug Product Development 33 2.6 Clinical Studies 36 2.7 Summary 39 References 39 CHAPTER 3 OLMESARTAN MEDOXOMIL: AN ANGIOTENSIN II RECEPTOR BLOCKER 45 Hiroaki Yanagisawa, Hiroyuki Koike, and Shin–ichiro Miura 3.1 Background 45 3.2 The Discovery of Olmesartan Medoxomil (Benicar) 47 3.3 Characteristics of Olmesartan 53 3.4 Binding Sites of Omlersartan to the AT1 Receptor and Its Inverse Agonoist Activity 56 3.5 Practical Preparation of Olmesartan Medoxomil 58 3.6 Preclinical Studies 58 3.7 Clinical Studies 62 3.8 Conclusion 63 References 64 CHAPTER 4 DISCOVERY OF HETEROCYCLIC PHOSPHONIC ACIDS AS NOVELAMPMIMICS THAT ARE POTENT AND SELECTIVE FRUCTOSE–1,6–BISPHOSPHATASE INHIBITORS AND ELICIT POTENT GLUCOSE–LOWERING EFFECTS IN DIABETIC ANIMALS AND HUMANS 67 Qun Dang and Mark D. Erion 4.1 Introduction 67 4.2 The Discovery of MB06322 69 4.3 Pharmacokinetic Studies of MB06322 82 4.4 Synthetic Routes to MB06322 83 4.5 Clinical Studies of MB06322 83 4.6 Summary 84 References 85 CHAPTER 5 SETTING THE PARADIGM OF TARGETED DRUGS FOR THE TREATMENT OF CANCER: IMATINIB AND NILOTINIB, THERAPIES FOR CHRONIC MYELOGENOUS LEUKEMIA 88 Paul W. Manley and Jürg Zimmermann 5.1 Introduction 88 5.2 Chronic Myelogenous Leukemia (CML) and Early Treatment of the Disease 89 5.3 Imatinib: A Treatment for Chronic Myelogenous Leukemia (CML) 92 5.4 The Need for New Inhibitorts of BCR–ABL1 and Development of Nilotinib 94 5.5 Conclusion 99 References 100 CHAPTER 6 AMRUBICIN, A COMPLETELY SYNTHETIC 9–AMINOANTHRACYCLINE FOR EXTENSIVE–DISEASE SMALL–CELL LUNG CANCER 103 Mitsuharu Hanada 6.1 Introduction 103 6.2 The Discovery of Amrubicin: The First Completely Synthetic Anthracycline 106 6.3 Toxicological Profile of Amrubicin 107 6.4 DNA Topoisomerase II Inhibition and Apoptosis Induction by Amrubicin 110 6.5 Amrubicin Metabolism: The Discovery of Amrubicinol 113 6.6 Improved Usage of Amrubicin 116 6.7 Clinical Trials 118 6.8 Conclusions 122 References 123 CHAPTER 7 THE DISCOVERY OF DUAL IGF–1R AND IR INHIBITOR FQIT FOR THE TREATMENT OF CANCER 127 Meizhong Jin, Elizabeth Buck, and Mark J. Mulvihill 7.1 Biological Rational for Targeting the IGF–1R/IR Pathway for Anti–Cancer Therapy 127 7.2 Discovery Of OSI–906 128 7.3 OSI–906 Back Up Efforts 131 7.4 The Discovery Of FQIT 131 7.5 In Vitro Profile of FQIT 140 7.6 Pharmacokinetic Properties of FQIT 144 7.7 In Vivo Profile of FQIT 146 7.8 Safety Assessment and Selectivity Profile of FQIT 148 7.9 Summary 150 Acknowledgments 151 References 151 CHAPTER 8 DISCOVERY AND DEVELOPMENT OF MONTELUKAST (SINGULAIR®) 154 Robert N. Young 8.1 Introduction 154 8.2 Drug Development Strategies 158 8.3 LTD4 Antagonist Program 159 8.4 The Discovery of Montelukast (Singulair®) 160 8.5 Synthesis of Montelukast 174 8.6 ADME Studies with MK–0476 (Montelukast) 179 8.7 Safety Assessment of Montelukast 180 8.8 Clinical Development of Montelukast 180 8.9 Summary 185 8.9.1 Impact on Society 185 8.9.2 Lessons Learned 186 8.10 Personal Impact 187 References 188 CHAPTER 9 DISCOVERY AND DEVELOPMENT OF MARAVIROC, A CCR5 ANTAGONIST FOR THE TREATMENT OF HIV INFECTION 196 Patrick Dorr, Blanda Stammen, and Elna van der Ryst 9.1 Background and Rationale 196 9.2 The Discovery of Maraviroc 199 9.3 Preclinical Studies 201 9.4 The Synthesis of Maraviroc 205 9.5 Nonclinical Safety and Toxicity Studies 206 9.6 Clinical Development of Maraviroc 207 9.7 Summary, Future Directions, and Challenges 214 Acknowledgments 217 References 217 CHAPTER 10 DISCOVERY OF ANTIMALARIAL DRUG ARTEMISININ AND BEYOND 227 Weiwei Mao, Yu Zhang, and Ao Zhang 10.1 Introduction: Natural Products in Drug Discovery 227 10.2 Natural Product Drug Discovery in China 227 10.3 Discovery of Artemisinin: Background, Structural Elucidation and Pharmacological Evaluation 228 10.4 The Synthesis of Artemisinin 232 10.5 SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether 238 10.6 Development of Artemether 248 10.7 Conclusion and Perspective 250 Acknowledgment 250 References 251 CHAPTER 11 DISCOVERY AND PROCESS DEVELOPMENT OF MK–4965, A POTENT NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR 257 Yong–Li Zhong, Thomas J. Tucker, and Jingjun Yin 11.1 Introduction 257 11.2 The Discovery of MK–4965 260 11.3 Preclinical and Clinical Studies of MK–4965 (19) 266 11.4 Summary of Back–Up SAR Studies of MK–4965 Series 266 11.5 Process Development of MK–4965 (19) 267 11.6 Conclusion 290 Acknowledgments 291 References 291 CHAPTER 12 DISCOVERY OF BOCEPREVIR AND NARLAPREVIR: THE FIRST AND SECOND GENERATION OF HCV NS3 PROTEASE INHIBITORS 296 Kevin X. Chen and F. George Njoroge 12.1 Introduction 296 12.2 HCV NS3 Protease Inhibitors 298 12.3 Research Operation Plan and Biological Assays 302 12.4 Discovery of Boceprevir 303 12.5 Profile of Boceprevir 317 12.6 Clinical Development and Approval of Boceprevir 319 12.7 Synthesis of Boceprevir 319 12.8 Discovery of Narlaprevir 322 12.9 Summary 329 References 330 CHAPTER 13 THE DISCOVERYOFSAMSCA— (TOLVAPTAN):THEFIRST ORAL NONPEPTIDE VASOPRESSIN RECEPTOR ANTAGONIST 336 Kazumi Kondo and Yoshitaka Yamamura 13.1 Background Information about the Disease 336 13.2 Biological Rational 337 13.3 Lead Generation Strategies: The Discovery of Mozavaptan 338 13.4 Lead Optimization: From Mozavaptan to Tolvaptan 347 13.5 Pharmacological Profiles of Tolvaptan 350 13.6 Drug Development 353 13.7 Summary Focusing on Lessons Learned 356 Acknowledgments 357 References 357 CHAPTER 14 SILODOSIN (URIEF®, RAPAFLO®, THRUPAS®, UROREC®, SILODIX???): A SELECTIVE ??1A ADRENOCEPTOR ANTAGONIST FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 360 Masaki Yoshida, Imao Mikoshiba, Katsuyoshi Akiyama, and Junzo Kudoh 14.1 Background Information 360 14.2 The Discovery of Silodosin 362 14.3 Pharmacology of Silodosin 369 14.4 Metabolism of Silodosin 373 14.5 Pharmacokinetics of Silodosin 376 14.6 Toxicology of Silodosin 379 14.7 Clinical Trials 382 14.8 Summary: Key Lessons Learned 388 References 389 CHAPTER 15 RALOXIFENE: A SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM) 392 Jeffrey A. Dodge and Henry U. Bryant 15.1 Introduction: SERMs 392 15.2 The Benzothiophene Scaffold: A New Class of SERMs 394 15.3 Assays for Biological Evaluation of Tissue Selectivity 394 15.4 Benzothiophene Structure Activity 395 15.5 The Synthesis of Raloxifene 401 15.6 SERM Mechanism 402 15.7 Raloxifene Pharmacology 405 15.8 Summary 411 References 411 APPENDIX I SMALL MOLECULE DRUG DISCOVERY AND DEVELOPMENT PARADIGM 417 APPENDIX II GLOSSARY 419 APPENDIX III ABBREVIATIONS 432 INDEX 443