Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

The discovery and SAR of a novel series of HCV polymerase inhibitors are described. A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure–activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.