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.

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 EC(50) as low as 1.7 microM). 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.

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.