Article pubs.acs.org/jmc
The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection Paul M. Scola,*,† Li-Qiang Sun,*,† Alan Xiangdong Wang,† Jie Chen,† Ny Sin,† Brian L. Venables,† Sing-Yuen Sit,† Yan Chen,† Anthony Cocuzza,† Donna M. Bilder,† Stanley V. D’Andrea,† Barbara Zheng,† Piyasena Hewawasam,† Yong Tu,† Jacques Friborg,‡ Paul Falk,‡ Dennis Hernandez,‡ Steven Levine,‡ Chaoqun Chen,‡ Fei Yu,‡ Amy K. Sheaffer,‡ Guangzhi Zhai,‡ Diana Barry,‡ Jay O. Knipe,∥ Yong-Hae Han,∥ Richard Schartman,∥ Maria Donoso,∥ Kathy Mosure,∥ Michael W. Sinz,∥ Tatyana Zvyaga,# Andrew C. Good,§ Ramkumar Rajamani,§ Kevin Kish,◆ Jeffrey Tredup,◆ Herbert E. Klei,◆ Qi Gao,○ Luciano Mueller,∇ Richard J. Colonno,‡ Dennis M. Grasela,⊥ Stephen P. Adams,∥ James Loy,∥ Paul C. Levesque,∥ Huabin Sun,∥ Hong Shi,∥ Lucy Sun,∥ William Warner,∥ Danshi Li,∥ Jialong Zhu,∥ Nicholas A. Meanwell,† and Fiona McPhee‡ †
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut, 06492, United States ‡ Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut, 06492, United States § Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut, 06492, United States ∥ Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut, 06492, United States ⊥ Department of Clinical Development Infectious Disease, Bristol-Myers Squibb Research and Development, PO Box 5400 Princeton, New Jersey, 08543, United States # Department of Lead Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut, 06492, United States ∇ Department of Mechanistic Biochemistry, Bristol-Myers Squibb Research and Development, PO Box 5400 Princeton, New Jersey, 08543, United States ○ Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development, 1 Squibb Drive, New Brunswick, New Jersey, 08903, United States ◆ Department of Protein Science and Structure, Bristol-Myers Squibb Research and Development, PO Box 5400 Princeton, New Jersey, 08543, United States ABSTRACT: The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure−activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
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INTRODUCTION
improved potency in the whole cell replicon assays compared to the corresponding carboxylic acid progenitor, an observation
We have described the discovery of the hepatitis C virus (HCV) NS3/4A protease inhibitor BMS-605339 (1, Figure 1), which was derived from a tripeptidic acylsulfonamide chemotype.1 This chemical series introduced the cyclopropyl acylsulfonamide P1′ moiety, a structural element that confers © 2014 American Chemical Society
Special Issue: HCV Therapies Received: February 24, 2014 Published: February 24, 2014 1730
dx.doi.org/10.1021/jm500297k | J. Med. Chem. 2014, 57, 1730−1752
Journal of Medicinal Chemistry
Article
findings, the objective of the present work was the identification of a compound with preclinical antiviral and pharmacokinetic properties similar to 1 but with a CV profile that held minimal risk for side effects. More specifically, the immediate research objective was the identification of a clinical candidate with high potency toward GT 1a and 1b subtype replicons (EC50
