Synthesis and biological evaluation of a novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection

Abstract A novel β-D-2′-deoxy-2′-α-fluoro-2′-β- C -(fluoromethyl)uridine phosphoramidate prodrug ( 1 ) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC 50  = 0.18–1.13 μM) with low cytotoxicity (CC 50  > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.