Discovery of a Series of 2′-α-Fluoro,2′-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus

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.