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) |
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Authors: | Pierre L Beaulieu Michael Bös Michael G Cordingley Catherine Chabot Gulrez Fazal Michel Garneau James R Gillard Eric Jolicoeur Steven Laplante Ginette McKercher Martin Poirier Marc-André Poupart Youla S Tsantrizos Jianmin Duan George Kukolj |
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Affiliation: | Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada. |
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Abstract: | 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. |
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