title: Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection.
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.
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Chang
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Donghui
authors.initials: D
authors.lastname: Bao
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Byoung-Kwon
authors.initials: BK
authors.lastname: Chun
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Devan
authors.initials: D
authors.lastname: Naduthambi
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Dhanapalan
authors.initials: D
authors.lastname: Nagarathnam
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: P Ganapati
authors.initials: PG
authors.lastname: Reddy
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Hai-Ren
authors.initials: HR
authors.lastname: Zhang
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Shalini
authors.initials: S
authors.lastname: Bansal
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Espiritu
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Meg
authors.initials: M
authors.lastname: Keilman
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lam
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Congrong
authors.initials: C
authors.lastname: Niu
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Holly Micolochick
authors.initials: HM
authors.lastname: Steuer
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540-6608, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
keywords: NS5B polymerase; PSI-353661; antivirals; hepatitis C virus; nucleoside; phosphoramidate; prodrug; triphosphate