2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture

Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2′-Cl,2′-F-uridine phosphoramidate nucleotide <b>16</b>, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate <b>16</b> in its 5′-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate <b>16</b>-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate <b>16</b> a prospective candidate for further studies to establish its potential value as a new anti-HCV agent