We report the synthesis and biological
evaluation of a series of
4′-fluoro-2′-C-substituted uridines.
Triphosphates of the uridine analogues exhibited a potent inhibition
of hepatitis C virus (HCV) NS5B polymerase with IC50 values
as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate
prodrugs of these uridine analogues demonstrated a very potent activity
with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside
triphosphate in vitro in primary human hepatocytes and Huh-7 cells
as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed
promising results in phase 1 and 2 trials.