Complete Accounts of Integrated Drug Discovery and Development Recent Examples from the Pharmaceutical Industry, Volume 3

Case studies from the pharmaceutical industry

This book describes the continuum from discovery to development. Readers will learn how recent drugs, including grazoprevir, melflufen, relebactam, and tesirine, were developed. The book highlights emerging concepts, new developments, and challenges during the discovery process. Well-known authors from the pharmaceutical industry provide an inside look to traditionally closed-door procedures. Profssional chemists and students alike will find these accounts extremely valuable.

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.

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).

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.

Preface

Chapter 1: Discovery and Chemical Development of the Use-Dependent Sodium Channel Blocker Vixotrigine for the Treatment of Pain, David R. Witty, David T. MacPherson, Gerard M. P. Giblin, Michael T. Williams, Robbie Chen, Vinny Couming, John Guzowski, Erwin Irdam, William F. Kiesman, Daw-Iong Albert
Kwok, Wenli Liang, Tamera L. Mack, Erin M. O'Brien, Suzanne M. Opalka, Daniel Patience, Stefan Sahli, Donald G. Walker, and Frederick Osei-Yeboah
Chapter 2: The Discovery and Chemical Development of BMS-919373: A Selective IKur Inhibitor for the Potential Treatment of Atrial Fibrillation, Heather J. Finlay, Scott A. Savage, Jason M. Stevens, Steven R. Wisniewski, and Miao Yu
Chapter 3: Discovery and Development of Omecamtiv Mecarbil: A Novel Cardiac Myosin Activator for the Potential Treatment of Systolic Heart Failure, Bradley P. Morgan, Seb Caille, and Shawn D. Walker
Chapter 4: Identification and Development of AMG 986: A Potent and Efficacious APJ Agonist for the Treatment of Heart Failure, Matthew R. Kaller, Paul Dransfield, Robert P. Farrell, and Ted C. Judd
Chapter 5: Melflufen: A Journey from Discovery to Multi-Kilogram Production, Fredrik Lehmann and Johan Wennerberg
Chapter 6: Discovery and Chemical Development of S 44563, a Dual Bcl-2/Bcl-xL Inhibitor, Christophe Hardouin and Jerome-Benoit Starck
Chapter 7: Discovery and Chemical Development of Tesirine: An Antitumor Pyrrolobenzodiazepine Antibody-Drug Conjugate Drug-Linker, Arnaud C. Tiberghien and Jeremy S. Parker
Chapter 8: Discovery and Chemical Development of Relebactam: A Potent Beta-Lactamase Inhibitor in Combination with PrimaxinR for the Treatment of Serious and Antibiotic-Resistant Bacterial Infections, Feng Xu, Benjamin D. Sherry, and Timothy A. Blizzard
Chapter 9: Discovery and Chemical Development of Grazoprevir: An HCV NS3/4a Protease Inhibitor for the Treatment of the Hepatitis C Virus Infection, Feng Xu and John A. McCauley
Chapter 10: Discovery and Process Development of BIIB068: A Reversible Bruton’s Tyrosine Kinase (BTK) Inhibitor for the Treatment of Autoimmune Diseases, Bin Ma, Chaomin Li, Brian T. Hopkins, Lloyd Franklin, Robbie Chen, Tamera Mack, Daniel Patience, William F. Kiesman, and Erin M. O’Brien
Chapter 11: Discovery and Commercial Development of Cholesteryl Transfer Protein Inhibitor Evacetrapib, Nathan B. Mantlo and Scott A. Frank

Editor's Biographies
Author Index
Subject Index