735287-43-1Relevant articles and documents
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)
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
, p. 7650 - 7666,17 (2020/08/24)
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.
