Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection
Authors:
- 17 December 2010
- journal article
- letter
- Published by American Chemical Society (ACS) in ACS Medicinal Chemistry Letters
- Vol. 2 (2) , 130-135
Abstract
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.Keywords
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