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2′-Deoxy-2′-α-fluoro-2′-β-C-methyl 3′,5′-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: Discovery of PSI-352938

✍ Scribed by P. Ganapati Reddy; Donghui Bao; Wonsuk Chang; Byoung-Kwon Chun; Jinfa Du; Dhanapalan Nagarathnam; Suguna Rachakonda; Bruce S. Ross; Hai-Ren Zhang; Shalini Bansal; Christine L. Espiritu; Meg Keilman; Angela M. Lam; Congrong Niu; Holly Micolochick Steuer; Phillip A. Furman; Michael J. Otto; Michael J. Sofia

Book ID: 104004998
Publisher: Elsevier Science
Year: 2010
Tongue: English
Weight: 808 KB
Volume: 20
Category: Article
ISSN: 0960-894X
DOI: 10.1016/j.bmcl.2010.10.035

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✦ Synopsis

A series of novel 2 0 -deoxy-2 0 -a-fluoro-2 0 -b-C-methyl 3 0 ,5 0 -cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).

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