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ID: ALA4007470
Journal: Bioorg Med Chem Lett
Title: Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.
Authors: Kirschberg TA, Metobo S, Clarke MO, Aktoudianakis V, Babusis D, Barauskas O, Birkus G, Butler T, Byun D, Chin G, Doerffler E, Edwards TE, Fenaux M, Lee R, Lew W, Mish MR, Murakami E, Park Y, Squires NH, Tirunagari N, Wang T, Whitcomb M, Xu J, Yang H, Ye H, Zhang L, Appleby TC, Feng JY, Ray AS, Cho A, Kim CU.
Abstract: A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
CiteXplore: 28274633