2. Academic Validation
  3. Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection

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

Affiliation

  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14391
    NS5B Polymerase Inhibitor
    HCV