Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection

Hepatitis C virus afflicts approximately 180 million people
worldwide, and the development of direct acting antivirals may offer
substantial benefit compared to the current standard of care. Accordingly,
prodrugs of 2′-deoxy-2′-fluoro-2′-C-methylguanosine monophosphate analogues were prepared and evaluated
for their anti-HCV efficacy and tolerability. These prodrugs demonstrated
>1000 fold greater potency than the parent nucleoside in a cell-based
replicon assay as a result of higher intracellular triphosphate levels.
Further optimization led to the discovery of the clinical candidate
PSI-353661, which has demonstrated strong in vitro inhibition against HCV without cytotoxicity and equipotent activity
against both the wild type and the known S282T nucleoside/tide resistant
replicon. PSI-353661 is currently in preclinical development for the
treatment of HCV.