Case Studies in Modern Drug Discovery and Development

Xianhai Huang, PhD, is a Principal Scientist at Merck Research Laboratories. Dr. Huang is the inventor or co-inventor on more than forty patents and patent applications. As a mentor in the Schering-Plough chemistry postdoctoral program, Dr. Huang and his group discovered novel synthetic applications of (diacetoxyiodo) benzene and successfully applied the methodology to the total synthesis of psymberin, an antitumor natural product.Robert G. Aslanian, PhD, is an adjunct professor of chemistry at William Paterson University and was formerly a Senior Director of Medicinal Chemistry with the Schering-Plough Research Institute and Merck Research Laboratories. Dr. Aslanian has over twenty-five years of experience in the pharmaceutical industry. He is co-inventor on thirty-eight U.S. patents and coauthor on sixty-seven scientific articles and reviews.

• Preface xvContributors xviiChapter 1 Introduction: Drug Discovery in Difficult Times 1Malcolm MacCossChapter 2 Discovery and Development of The DPP-4 Inhibitor Januvia® (SITA-GLIPTIN) 10Emma R. Parmee, Ranabir SinhaRoy, Feng Xu, Jeffrey C. Givand, and Lawrence A. Rosen2.1 Introduction 102.2 DPP-4 Inhibition as a Therapy for Type 2 Diabetes: Identification of Key Determinants for Efficacy and Safety 102.3 Medicinal Chemistry Program 202.4 Synthetic and Manufacturing Routes to Sitagliptin 272.5 Drug Product Development 332.6 Clinical Studies 362.7 Summary 39References 39Chapter 3 Olmesartan Medoxomil: An Angiotensin II Receptor Blocker 45Hiroaki Yanagisawa, Hiroyuki Koike, and Shin-ichiro Miura3.1 Background 453.1.1 Introduction 453.1.2 Prototype of Orally Active ARBs 463.2 The Discovery of Olmesartan Medoxomil (Benicar) 473.3 Characteristics of Olmesartan 533.4 Binding Sites of Omlersartan to the AT1 Receptor and Its Inverse Agonoist Activity 563.5 Practical Preparation of Olmesartan Medoxomil 583.6 Preclinical Studies 583.7 Clinical Studies 623.8 Conclusion 63References 64Chapter 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 67Qun Dang and Mark D. Erion4.1 Introduction 674.2 The Discovery of MB06322 694.3 Pharmacokinetic Studies of MB06322 824.4 Synthetic Routes to MB06322 834.5 Clinical Studies of MB06322 834.6 Summary 84References 85Chapter 5 Setting The Paradigm of Targeted Drugs for The Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukemia 88Paul W. Manley and Jurg Zimmermann5.1 Introduction 885.2 Chronic Myelogenous Leukemia (CML) and Early Treatment of the Disease 895.3 Imatinib: A Treatment for Chronic Myelogenous Leukemia (CML) 925.4 The Need for New Inhibitorts of BCR-ABL1 and Development of Nilotinib 945.5 Conclusion 99References 100Chapter 6 Amrubicin, A Completely Synthetic 9-Aminoanthracycline for Extensive-Disease Small-Cell Lung Cancer 103Mitsuharu Hanada6.1 Introduction 1036.2 The Discovery of Amrubicin: The First Completely Synthetic Anthracycline 1066.3 Toxicological Profile of Amrubicin 1076.4 DNA Topoisomerase II Inhibition and Apoptosis Induction by Amrubicin 1106.5 Amrubicin Metabolism: The Discovery of Amrubicinol 1136.6 Improved Usage of Amrubicin 1166.7 Clinical Trials 1186.8 Conclusions 122References 123Chapter 7 The Discovery of Dual IGF-1R and IR Inhibitor FQIT for the Treatment of Cancer 127Meizhong Jin, Elizabeth Buck, and Mark J. Mulvihill7.1 Biological Rational for Targeting the IGF-1R/IR Pathway for Anti-Cancer Therapy 1277.2 Discovery of OSI-906 1287.3 OSI-906 Back Up Efforts 1317.4 The Discovery of FQIT 1317.5 In Vitro Profile of FQIT 1407.6 Pharmacokinetic Properties of FQIT 1447.7 In Vivo Profile of FQIT 1467.8 Safety Assessment and Selectivity Profile of FQIT 1487.9 Summary 150Acknowledgments 151References 151Chapter 8 Discovery and Development of Montelukast (Singulair®) 154Robert N. Young8.1 Introduction 1548.2 Drug Development Strategies 1588.3 LTD4 Antagonist Program 1598.4 The Discovery of Montelukast (Singulair®) 1608.5 Synthesis of Montelukast 1748.6 ADME Studies with MK-0476 (Montelukast) 1798.7 Safety Assessment of Montelukast 1808.8 Clinical Development of Montelukast 1808.9 Summary 1858.10 Personal Impact 187References 188Chapter 9 Discovery and Development of Maraviroc, A CCR5 Antagonist for the Treatment of HIV Infection 196Patrick Dorr, Blanda Stammen, and Elna van der Ryst9.1 Background and Rationale 1969.2 The Discovery of Maraviroc 1999.3 Preclinical Studies 2019.4 The Synthesis of Maraviroc 2059.5 Nonclinical Safety and Toxicity Studies 2069.6 Clinical Development of Maraviroc 2079.7 Summary, Future Directions, and Challenges 214Acknowledgments 217References 217Chapter 10 Discovery of Antimalarial Drug Artemisinin and Beyond 227Weiwei Mao, Yu Zhang, and Ao Zhang10.1 Introduction: Natural Products in Drug Discovery 22710.2 Natural Product Drug Discovery in China 22710.3 Discovery of Artemisinin: Background, Structural Elucidation and Pharmacological Evaluation 22810.4 The Synthesis of Artemisinin 23210.5 SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether 23810.6 Development of Artemether 24810.7 Conclusion and Perspective 250Acknowledgment 250References 251Chapter 11 Discovery and Process Development of MK-4965, A Potent Nonnucleoside Reverse Transcriptase Inhibitor 257Yong-Li Zhong, Thomas J. Tucker, and Jingjun Yin11.1 Introduction 25711.2 The Discovery of MK-4965 26011.3 Preclinical and Clinical Studies of MK-4965 (19) 26611.4 Summary of Back-Up SAR Studies of MK-4965 Series 26611.5 Process Development of MK-4965 (19) 26711.6 Conclusion 290Acknowledgments 291References 291Chapter 12 Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors 296Kevin X. Chen and F. George Njoroge12.1 Introduction 29612.2 HCV NS3 Protease Inhibitors 29812.3 Research Operation Plan and Biological Assays 30212.4 Discovery of Boceprevir 30312.5 Profile of Boceprevir 31712.6 Clinical Development and Approval of Boceprevir 31912.7 Synthesis of Boceprevir 31912.8 Discovery of Narlaprevir 32212.9 Summary 329References 330Chapter 13 The Discoveryofsamsca® (Tolvaptan): Thefirst Oral Nonpeptide Vasopressin Receptor Antagonist 336Kazumi Kondo and Yoshitaka Yamamura13.1 Background Information about the Disease 33613.2 Biological Rational 33713.3 Lead Generation Strategies: The Discovery of Mozavaptan 33813.4 Lead Optimization: From Mozavaptan to Tolvaptan 34713.5 Pharmacological Profiles of Tolvaptan 35013.6 Drug Development 35313.7 Summary Focusing on Lessons Learned 356Acknowledgments 357References 357Chapter 14 Silodosin (Urief®, Rapaflo®, Thrupas®, Urorec®, Silodix®): A Selective α1A Adrenoceptor Antagonist for the Treatment of Benign Prostatic Hyperplasia 360Masaki Yoshida, Imao Mikoshiba, Katsuyoshi Akiyama, and Junzo Kudoh14.1 Background Information 36014.2 The Discovery of Silodosin 36214.3 Pharmacology of Silodosin 36914.4 Metabolism of Silodosin 37314.5 Pharmacokinetics of Silodosin 37614.6 Toxicology of Silodosin 37914.7 Clinical Trials 38214.8 Summary: Key Lessons Learned 388References 389Chapter 15 Raloxifene: A Selective Estrogen Receptor Modulator (SERM) 392Jeffrey A. Dodge and Henry U. Bryant15.1 Introduction: SERMs 39215.2 The Benzothiophene Scaffold: A New Class of SERMs 39415.3 Assays for Biological Evaluation of Tissue Selectivity 39415.4 Benzothiophene Structure Activity 39515.5 The Synthesis of Raloxifene 40115.6 SERM Mechanism 40215.7 Raloxifene Pharmacology 40515.8 Summary 411References 411Appendix I Small Molecule Drug Discovery and Development Paradigm 417Appendix II Glossary 419Appendix III Abbreviations 432Index 443

“This book will enrich the collection of medicinal chemists or pharmacologists involved in active drug discovery research, as well as students with a passion for pursuing a career in drug discovery.”  (Doody’s, 22 February 2013) "A well-made glossary is available in the appendix, which defines the dozens of terms that a medicinal chemist will encounter in his/her career. . . This book demonstrates yet again the need for new, better medicines and the reasons for the high cost of drug research. An enjoyable read!.”  (ChemMedChem, 1 January 2013)