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Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.

A variety of 2,6-modified purine 2'-C-methylribonucleosides and their phosphoramidate prodrugs were synthesized and evaluated for inhibition of HCV RNA replication in Huh-7 cells and for cytotoxicity in various cell lines. Cellular pharmacology and HCV polymerase incorporation studies on the most potent and selective compound are reported.

A novel anti-hepatitis C virus (HCV) agent, N(3),5'-cyclo-4-(beta-D-ribofuranosyl)-vic-triazolo[4,5-b]pyridinin-5-one, was identified, and the structure was confirmed by chemical synthesis from 2-hydroxy-5-nitropyridine.