Benzimidazole Thumb Pocket I finger-loop inhibitors of HCV NS5B polymerase: Improved drug-like properties through C-2 SAR in three sub-series

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• 作者：Pierre L. Beaulieu ; Nathalie Dansereau ; Jianmin Duan ; Michel Garneau ; James Gillard ; Ginette McKercher ; Steven LaPlante ; Lisette Lagacé ; e ; Louise Thauvette ; George Kukolj
• 关键词：Hepatitis C virus ; HCV ; NS5B polymerase ; Allosteric inhibitors ; Replicon inhibitors ; Benzimidazole ; Antivirals
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：15 March 2010
• 年：2010
• 卷：20
• 期：6
• 页码：1825-1829
• 全文大小：723 K

文摘

SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides. The consistent SAR among the three sub-series suggest a common binding mode to the Thumb Pocket I allosteric site. New inhibitors with sub-micromolar cell-based replicon potency and improved ‘drug-like’ features are disclosed along with preliminary characterization of their ADME-PK profile.