390809-69-5Relevant academic research and scientific papers
Benzimidazole Thumb Pocket I finger-loop inhibitors of HCV NS5B polymerase: Improved drug-like properties through C-2 SAR in three sub-series
Beaulieu, Pierre L.,Dansereau, Nathalie,Duan, Jianmin,Garneau, Michel,Gillard, James,McKercher, Ginette,LaPlante, Steven,Lagacée, Lisette,Thauvette, Louise,Kukolj, George
scheme or table, p. 1825 - 1829 (2010/07/08)
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.
Non-nucleoside benzimidazole-based allosteric inhibitors of the hepatitis C virus NS5B polymerase: Inhibition of subgenomic hepatitis C virus RNA replicons in huh-7 cells
Beaulieu, Pierre L.,Bousquet, Yves,Gauthier, Jean,Gillard, James,Marquis, Martin,McKercher, Ginette,Pellerin, Charles,Valois, Serge,Kukolj, George
, p. 6884 - 6892 (2007/10/03)
A previously disclosed series of non-nucleoside allosteric inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) was optimized to yield novel compounds with improved physicochemical properties and activity in cell-based assays. Replacement of ionizable carboxylic acids with neutral substituents in lead compounds produced inhibitors with cellular permeability and antiviral activity in a cell-based assay of subgenomic HCV RNA replication (replicon EC50 as low as 1.7 μM. The improvement in potency in this ex vivo model of HCV RNA replication validates, in part, the mechanism by which this class of allosteric benzimidazole derivatives inhibits the polymerase and represents a significant step forward in the discovery of novel HCV therapeutics.
Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: Discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency
Beaulieu, Pierre L.,Boes, Michael,Bousquet, Yves,DeRoy, Patrick,Fazal, Gulrez,Gauthier, Jean,Gillard, James,Goulet, Sylvie,McKercher, Ginette,Poupart, Marc-Andre,Valois, Serge,Kukolj, George
, p. 967 - 971 (2007/10/03)
Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.
