Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)

作者：Beaulieu Pierre L^*; Boes Michael; Cordingley Michael G; Chabot Catherine; Fazal Gulrez; Garneau Michel; Gillard James R; Jolicoeur Eric; LaPlante Steven; McKercher Ginette; Poirier Martin; Poupart Marc Andre; Tsantrizos Youla S; Duan Jianmin; Kukolj George

来源：Journal of Medicinal Chemistry, 2012, 55(17): 7650-7666.

DOI：10.1021/jm3006788

Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.

• 出版日期2012-9-13