Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

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• 作者：Paul M. Scola ; Alan Xiangdong Wang ; Andrew C. Good ; Li-Qiang Sun ; Keith D. Combrink ; Jeffrey A. Campbell ; Jie Chen ; Yong Tu ; Ny Sin ; Brian L. Venables ; Sing-Yuen Sit ; Yan Chen ; Anthony Cocuzza ; Donna M. Bilder ; Stanley D鈥橝ndrea ; Barbara Zheng ; Piyasena Hewawasam ; Min Ding ; Jan Thuring ; Jianqing Li ; Dennis Hernandez ; Fei Yu ; Paul Falk ; Guangzhi Zhai ; Amy K. Sheaffer ; Chaoqun Chen ; Min S. Lee ; Diana Barry ; Jay O. Knipe ; Wenying Li ; Yong-Hae Han ; Susan Jenkins ; Christoph Gesenberg ; Qi Gao ; Michael W. Sinz ; Kenneth S. Santone ; Tatyana Zvyaga ; Ramkumar Rajamani ; Herbert E. Klei ; Richard J. Colonno ; Dennis M. Grasela ; Eric Hughes ; Caly Chien ; Stephen Adams ; Paul C. Levesque ; Danshi Li ; Jialong Zhu ; Nicholas A. Meanwell ; Fiona McPhee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1708-1729
• 全文大小：900K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1鈥?site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.