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

  • ACS Med Chem Lett. 2010 Dec 17;2(2):130-5. doi: 10.1021/ml100209f.
Wonsuk Chang  1 ,  Donghui Bao  1 ,  Byoung-Kwon Chun  1 ,  Devan Naduthambi  1 ,  Dhanapalan Nagarathnam  1 ,  Suguna Rachakonda  1 ,  P Ganapati Reddy  1 ,  Bruce S Ross  1 ,  Hai-Ren Zhang  1 ,  Shalini Bansal  1 ,  Christine L Espiritu  1 ,  Meg Keilman  1 ,  Angela M Lam  1 ,  Congrong Niu  1 ,  Holly Micolochick Steuer  1 ,  Phillip A Furman  1 ,  Michael J Otto  1 ,  Michael J Sofia  1
Affiliations
  • 1. Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
PMID: 24900291 DOI: 10.1021/ml100209f
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
NS5B polymerase; PSI-353661; antivirals; hepatitis C virus; nucleoside; phosphoramidate; prodrug; triphosphate.
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