Case Studies in Modern Drug Discovery and Development (eBook, PDF)

Redaktion: Huang, Xianhai; Aslanian, Robert G.

• Format: PDF

Produktbeschreibung

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.

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 480
• Erscheinungstermin: 19. April 2012
• Englisch
• ISBN-13: 9781118219706
• Artikelnr.: 38242105

Autorenporträt

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.

Inhaltsangabe

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(TM) (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(r)) 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(r)) 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(r), RAPAFLO(r), THRUPAS(r), UROREC(r), SILODIX(TM)): A
SELECTIVE alpha1A 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