Case Studies in Modern Drug Discovery and Development

Learn why some drug discovery and development efforts succeed . . . and others fail

Written by international experts in drug discovery and development, this book sets forth carefully researched and analyzed case studies of both successful and failed drug discovery and development efforts, enabling medicinal chemists and pharmaceutical scientists to learn from actual examples. Each case study focuses on a particular drug and therapeutic target, guiding readers through the drug discovery and development process, including drug design rationale, structure–activity relationships, pharmacology, drug metabolism, biology, and clinical studies.

Case Studies in Modern Drug Discovery and Development begins with an introductory chapter that puts into perspective the underlying issues facing the pharmaceutical industry and provides insight into future research opportunities. Next, there are fourteen detailed case studies, examining:

All phases of drug discovery and development from initial idea to commercialization

Some of today′s most important and life–saving medications

Drugs designed for different therapeutic areas such as cardiovascular disease, infection, inflammation, cancer, metabolic syndrome, and allergies

Examples of prodrugs and inhaled drugs

Reasons why certain drugs failed to advance to market despite major research investments

Each chapter ends with a list of references leading to the primary literature. There are also plenty of tables and illustrations to help readers fully understand key concepts, processes, and technologies.

Improving the success rate of the drug discovery and development process is paramount to the pharmaceutical industry. With this book as their guide, readers can learn from both successful and unsuccessful efforts in order to apply tested and proven science and technologies that increase the probability of success for new drug discovery and development projects.

PREFACE xv

CONTRIBUTORS xvii

CHAPTER 1 INTRODUCTION: DRUG DISCOVERY IN DIFFICULTTIMES 1
Malcolm MacCoss

CHAPTER 2 DISCOVERY AND DEVELOPMENT OF THE DPP–4INHIBITOR 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 IIRECEPTOR BLOCKER 45
Hiroaki Yanagisawa, Hiroyuki Koike, and Shin–ichiroMiura

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 ItsInverse 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 ACIDSAS NOVELAMPMIMICS THAT ARE POTENT AND SELECTIVEFRUCTOSE–1,6–BISPHOSPHATASE INHIBITORS AND ELICIT POTENTGLUCOSE–LOWERING EFFECTS IN DIABETIC ANIMALS AND HUMANS67
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 FORTHE TREATMENT OF CANCER: IMATINIB AND NILOTINIB, THERAPIES FORCHRONIC MYELOGENOUS LEUKEMIA 88
Paul W. Manley and Jürg Zimmermann

5.1 Introduction 88

5.2 Chronic Myelogenous Leukemia (CML) and Early Treatment ofthe 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 ofNilotinib 94

5.5 Conclusion 99

References 100

CHAPTER 6 AMRUBICIN, A COMPLETELY SYNTHETIC9–AMINOANTHRACYCLINE FOR EXTENSIVE–DISEASE SMALL–CELL LUNGCANCER 103
Mitsuharu Hanada

6.1 Introduction 103

6.2 The Discovery of Amrubicin: The First Completely SyntheticAnthracycline 106

6.3 Toxicological Profile of Amrubicin 107

6.4 DNA Topoisomerase II Inhibition and Apoptosis Induction byAmrubicin 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 IRINHIBITOR 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 forAnti–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, ACCR5 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 ARTEMISININAND 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, StructuralElucidation and Pharmacological Evaluation 228

10.4 The Synthesis of Artemisinin 232

10.5 SAR Studies of Structural Derivatives of Artemisinin: TheDiscovery 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 OFMK–4965, A POTENT NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR257
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 INHIBITORS296
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 RECEPTORANTAGONIST 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 Mozavaptan338

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 ): ASELECTIVE 1A ADRENOCEPTOR ANTAGONIST FORTHE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 360
Masaki Yoshida, Imao Mikoshiba, Katsuyoshi Akiyama, andJunzo 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 RECEPTORMODULATOR (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 Selectivity394

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 DEVELOPMENTPARADIGM 417

APPENDIX II GLOSSARY 419

APPENDIX III ABBREVIATIONS 432

INDEX 443

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.

This book will enrich the collection of medicinalchemists or pharmacologists involved in active drug discoveryresearch, as well as students with a passion for pursuing a careerin drug discovery.   (Doody s, 22 February2013) 

"A well–made glossary is available in the appendix, whichdefines the dozens of terms that a medicinal chemist will encounterin his/her career. . . This book demonstrates yet again the needfor new, better medicines and the reasons for the high cost of drugresearch. An enjoyable read!.   (ChemMedChem, 1January 2013)