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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• 作者：Pierre L. Beaulieu ; Michael B枚s ; Michael G. Cordingley ; Catherine Chabot ; Gulrez Fazal ; Michel Garneau ; James R. Gillard ; Eric Jolicoeur ; Steven LaPlante ; Ginette McKercher ; Martin Poirier ; Marc-Andr茅 Poupart ; Youla S. Tsantrizos ; Jianmin Duan ; George Kukolj
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7650-7666
• 全文大小：773K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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. 鈥淐assette鈥?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.