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The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.
Scola, Paul M; Sun, Li-Qiang; Wang, Alan Xiangdong; Chen, Jie; Sin, Ny; Venables, Brian L; Sit, Sing-Yuen; Chen, Yan; Cocuzza, Anthony; Bilder, Donna M; D'Andrea, Stanley V; Zheng, Barbara; Hewawasam, Piyasena; Tu, Yong; Friborg, Jacques; Falk, Paul; Hernandez, Dennis; Levine, Steven; Chen, Chaoqun; Yu, Fei; Sheaffer, Amy K; Zhai, Guangzhi; Barry, Diana; Knipe, Jay O; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W; Zvyaga, Tatyana; Good, Andrew C; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E; Gao, Qi; Mueller, Luciano; Colonno, Richard J; Grasela, Dennis M; Adams, Stephen P; Loy, James; Levesque, Paul C; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Meanwell, Nicholas A; McPhee, Fiona.
Affiliation
  • Scola PM; Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut, 06492, United States.
J Med Chem ; 57(5): 1730-52, 2014 Mar 13.
Article in En | MEDLINE | ID: mdl-24564672
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Sulfonamides / Hepatitis C / Viral Nonstructural Proteins / Isoquinolines Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2014 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Sulfonamides / Hepatitis C / Viral Nonstructural Proteins / Isoquinolines Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2014 Document type: Article Affiliation country: Estados Unidos