Case Studies in Modern Drug Discovery and Development

by Huang, Xianhai; Aslanian, Robert G.

• ISBN13: 9780470601815
• ISBN10: 0470601817
• Edition: 1st
• Format: Hardcover
• Copyright: 2012-05-29
• Publisher: Wiley

Summary

Using case studies of successful drug discoveries and launches, this book helps master the necessary knowledge of the drug discovery process. It includes pharmacology, drug metabolism, biology, drug development, and clinical studies. The introduction provides an overview of process, principles, and technologies and each chapter contains case studies that focus on one therapeutic target. It also offers stories from patients who have used the drugs covered as a way to illustrate the impact medicinal chemistry has on real life.

Author Biography

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.

Table of Contents

Preface
List of Contributors
Introduction: Drug Discovery in Difficult Times
Discovery and Development of the DPP-4 Inhibitor JANUVIA (Sitagliptin)
Introduction
DPP-4 Inhibition as a Therapy for Type	p. 2
Diabetes - Identification of Key Determinants for Efficacy and Safety
Medicinal Chemistry Program
Synthetic and Manufacturing Routes to Sitagliptin
Drug Product Development
Clinical Studies
Summary
References
Olmesartan Medoxomil, an Angiotensin II Receptor Blocker
Background
The discovery of olmesartan medoxomil (Benicar)
Characteristics of olmesartan
Binding sites of olmesartan to the AT1 receptor and its inverse agonist activity
Practical preparation of olmesartan medoxomil
Preclinical studies
Clinical studies
Conclusion
References
Discovery of Heterocyclic Phosphonic Acids as Novel AMP Mimics That Are Potent and Selective Fructose-1,6-bisphosphatase Inhibitors and Elicit Potent Glucose-lowering Effects in Diabetic Animals and Human
Introduction
The discovery of MB06322
Pharmacokinetic and toxicology studies of MB06322
Synthetic routes to MB06322
Clinical studies of MB06322
Summary
References
Setting the Paradigm of Targeted Drugs for the Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukaemia
Introduction
Chronic myelogenous leukaemia (CML) and early treatment of the disease
Imatinib a treatment for chronic myelogenous leukaemia (CML)
The need for new inhibitors of BCR-ABL1 and development of nilotinib
Conclusion
References
Amrubicin, a Completely Synthetic 9-Aminoanthracycline, for Extensive-disease Small-cell Lung Cancer
Introduction
The discovery of Amrubicin: the first completely synthetic anthracycline
Toxicological profile of amrubicin
DNA topoisomerase II inhibition and apoptosis induction by amrubicin
Amrubicin metabolism: the discovery of amrubicinol
Clinical trials
Conclusions
References
The Discovery of Dual IGF-1R and IR Inhibitor FQIT for the Treatment of Cancer	p. 1
Biological rational for targeting the IGF-1R/IR pathway for anti-cancer therapy	p. 2
Discovery of OSI-906	p. 3
OSI-906 back up efforts	p. 4
The discovery of FQIT	p. 5
In vitro profile of FQIT	p. 6
Pharmacokinetic properties of FQIT	p. 7
In vivo profile of FQIT	p. 8
Safety assessment and selectivity profile of FQIT	p. 9
Summary	p. 10
Acknowledgements	p. 11
References and notes
Discovery and Development of Montelukast (Singulair)
Introduction
Drug development strategies
LTD4 antagonist program
The discovery of montelukast (singulair)
Synthesis of montelukast
ADME studies with MK-0476 (montelukast)
Safety assessment of montelukast
Clinical development of montelukast
Summary
Personal impact
References
Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV Infection
Background and rationale
The discovery of maraviroc
Preclinical studies
The synthesis of maraviroc
Non-clinical safety and toxicity studies
Clinical development of maraviroc
Summary, future directions and challenges
Acknowledgement
References
Discovery of Antimalarial Drug Artemisinin and Beyond
Introduction: natural products in drug discovery
Natural product drug discovery in China
Discovery of artemisinin: background, structural elucidation and pharmacological evaluation
The synthesis of artemisinin
SAR studies of structural derivatives of artemisinin: the discovery of artemether
Development of artemether
Conclusion and perspective
Acknowledgment
References
Discovery and Process Development of MK-4965, a Potent Non-Nucleoside Reverse Transcriptase Inhibitor
Introduction
The discovery of MK-4965
Preclinical and clinical studies of MK-4965
Summary of back up SAR studies of MK 4965 series
Process Development of MK-4965 (19)
Conclusion
Acknowledgements
References
Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors
Introduction
HCV NS3 protease inhibitors
Research operation plan and biological assays
Discovery of boceprevir
Profile of boceprevir
Clinical development of boceprevir
Synthesis of boceprevir
Discovery of narlaprevir
Summary
References
The Discovery of Samsca (Tolvaptan): The First Oral Nonpeptide Vasopressin Receptor Antagonist
Background information about the disease
Biological rational
Lead generation strategies: the discovery of mozavaptan
Lead optimization: from mozavaptan to tolvaptan
Pharmacological profiles of tolvaptan
Drug development
Summary focusing on lessons learned
Silodosin (Urief, Rapaflo, Thrupas, Urorec, Silodix): a Selective a1A Adrenoceptor Antagonist for the Treatment of Benign Prostatic Hyperplasia
Background information
The discovery of silodosin
Pharmacology of silodosin
Metabolism of silodosin
Pharmacokinetics of silodosin
Toxicology of silodosin
Clinical trials
Summary: key lessons learned
References
Raloxifene: A Selective Estrogen Receptor Modulator (SERM)
Introduction: SERMs
The benzothiophene scaffold: a new class of SERMs
Assays for biological evaluation
Benzotiophene structure activity
The synthesis of raloxifene
SERM mechanism
Raloxifene pharmacology
Summary
References
Small Molecule Drug Discovery and Development Paradigm
Glossary
Abbreviations
Index
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