Complete Accounts of Integrated Drug Discovery and Development

Recent Examples from the Pharmaceutical Industry (Volume 1)

Ahmed F. Abdel-Magid (Redaktør) ; Jaan A. Pesti (Redaktør) ; Rajappa Vaidyanathan (Redaktør)

The chapters in this book are written to accentuate the interdependency and synergy between drug discovery and process development disciplines to advance a new chemical entity into clinical trials and eventually to the market. Les mer
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The chapters in this book are written to accentuate the interdependency and synergy between drug discovery and process development disciplines to advance a new chemical entity into clinical trials and eventually to the market. Due to the success of our previous books (Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage Process Development, Volumes 1 and 2), the editors sought to further arm experienced modern synthetic
organic chemists, and budding researchers perhaps still in universities with real world examples from the pharmaceutical industry.

In addition, the chapters contain citations of a large number of valuable selected references to the primary literature. The book highlights the tireless efforts of Discovery and Process Chemists, and their roles in the advancement of drug discovery and development. The editors were motivated to create this book by our appreciation of the value of chemical research by both Discovery and Process Chemists in producing new pharmaceutical entities. Their combined efforts make it possible to
introduce novel and effective drugs into the market to treat hundreds of millions of patients and alleviate their suffering, improve their quality of life and possibly save their lives from diseases and disorders.

The chapters presented in this book are written by a selected group of outstanding, highly accomplished Medicinal and Process Chemists with noted experiences and diverse backgrounds representing some of the top pharmaceutical companies. The chapters highlight examples of emerging concepts, new developments and challenges arising in the discovery of new drug candidates and the development of new practical synthetic chemistry processes to produce these drug candidates on large scale. The story
leading up to the discovery of each drug or drug candidate is presented by the Discovery Chemist(s), and then the Process Chemist(s) describe the development of the same drug to give the reader a complete story of drug discovery and development. The reader will experience a rare and unique opportunity
to obtain the complete perspectives of Discovery and Process Chemistry in a single book. While most of these topics have appeared in the primary literature where space is critical and brevity valued, the book permits the editors and contributors to tell the complete tales as stories, from start to finish or to the current state of the drug development.




1. Discovery and Development of GDC-0994: A Selective and Efficacious Small Molecule Inhibitor of ERK1/2
2. Preclinical Identification and Development of AM-6138: An Inhibitor of BACE1 for the Treatment of Alzheimer's Disease
3. Discovery and Chemical Development of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease
4. Discovery and Chemical Development of JNJ-50138803, a Clinical Candidate BACE1 Inhibitor
5. Discovery and Development of Ruzasvir: An Investigational Next Generation Pan-Genotype HCV Nonstructural Protein 5A (NS5A) Inhibitor for the Cure of Hepatitis C Virus Infections
6. AZD6564, Discovery of a Potent 5-Substituted Isoxazol-3-ol Fibrinolysis Inhibitor and Development of an Enantioselective Large-Scale Route for Its Preparation
7. Design and Development of the Glucokinase Activator AZD1656
8. Development of a Reversible P2Y12R Antagonist, AZD1283-Discovery Research and Large-Scale Chemistry
9. Discovery, Process Development, and Scale-Up of a Benzoxazepine-Containing mTor Inhibitor

Editors' Biographies
Author Index
Subject Index

Om forfatteren

Ahmed F. Abdel-Magid was born in Giza, Egypt in 1947. He received his Bachelor's degree (1969) and Master's degree (1973) from Cairo University (Cairo, Egypt) and his Ph.D. (1980) from Temple University (Philadelphia, PA USA). After postdoctoral appointments at the University of South Carolina (Columbia, SC) and SmithKline Beckman Pharmaceuticals (Philadelphia, PA), he worked at Drexel University (Philadelphia, PA) as Teaching/Research Associate
(1985-1986), then as an Adjunct Professor (1986-2006). He joined the Process Chemistry Department at Wyeth Laboratories as Senior Chemist (1986-1987), after which he moved to the Process Chemistry Group at Johnson & Johnson PRD (1987-2008) as a Senior Scientist and rose through the ranks to Senior Research Fellow. He
joined Therachem Research Medilab in 2009, where he holds the titles of Executive VP and Chief Scientific Officer. Organic Process Research was his focus for 32 years: he contributed to the development of more than 50 processes including 5

for the commercial manufacture of marketed drugs. He is the inventor of 28 issued patents, editor of 6 books, author of 40 publications and 130 medicinal chemistry patent highlights published in ACS Medicinal Chemistry Letters. He served as the Executive Officer and Chair of the 39th National Organic Chemistry Symposium (NOS) held at the University of Utah in June 2005. He also served as the National Program Chair and member of the Executive Committee of the Division of Organic Chemistry of the
ACS (2008-2014), and he is a Patent Panelist for ACS Medicinal Chemistry Letters (2012-Present). His awards include: the Philip B. Hofmann Award for Outstanding Research from Johnson & Johnson (1994), the Philadelphia Organic Chemists' Club Award for Outstanding Contributions to Organic Chemistry
(2007), the ACS-Philadelphia Section Award for Conspicuous Scientific Achievement Through Research (2013), and he is a Fellow of the American Chemical Society (Inaugural class, 2009).

Jaan A. Pesti was born

on Long Island, NY in 1954. He received his Bachelor's degree from Long Island University, Brooklyn, NY in 1976 and his Ph.D. in organic chemistry from Columbia University in the laboratories of Prof. Thomas Katz in 1981. Following postdoctoral research in synthetic organic chemistry at University of California, Berkeley from 1981-1983, he joined the staff of Dupont's Medical Products Division in Wilmington, DE and Deepwater, NJ, conducting research in process development from bench scale to
pilot plant manufacture. He later transitioned to Dupont Merck Pharmaceuticals, Dupont Pharmaceuticals, and joined Bristol-Myers Squibb Pharmaceuticals in 2001. He retired from BMS in 2013 after 30 years of service credited, but has worked for NAL Pharma and Gelest, Inc., and currently is part of PRG,
Inc. and EnginZyme AB. His career has focused on the process development of potential drugs and medical devices, including contributions to the processes to manufacture the marketed drugs losartan and efavirenz.

He was the Associate Editor for the journal Organic Process Research & Development from 2008-2016. He cofounded the conference series Balticum Organicum Syntheticum (BOS), held biennially in the Baltics since 2000, and the symposium series Process Chemistry: New Developments in Pharmaceutical Process Development, held biennially at ACS National meetings.

Rajappa Vaidyanathan was born in Madras, India. He obtained his Bachelor's degree from Loyola College, Madras, and his Master's from the Indian Institute of Technology, Madras. He completed his Ph.D. in 1998 from the University of California, Irvine, working in the laboratories of Prof. Scott Rychnovsky. After a postdoctoral appointment at Eli Lilly and Company, he joined the Chemical Process R&D group of Pharmacia Corporation, Kalamazoo, MI, and subsequently Pfizer in
Groton, CT. During this period, he led several interdisciplinary teams in the discovery and development of practical, environmentally responsible processes for New Chemical

Entities, three of which were commercialized as approved drugs (sunitinib, tofacitinib, and bosutinib). He is currently Group Director and Head of Chemical Development and API Supply at Bristol-Myers Squibb in Bangalore, India. He has won numerous awards, most notably the American Chemical Society's "Heroes of Chemistry" Award (2015). Since 2012, he has been co-chairing the biennial symposium series Process Chemistry: The Role of Organic Synthesis in Early Clinical Drug Development at the ACS
National Meetings.