Kirschberg Thorsten A, Metobo Sammy, Clarke Michael O, Aktoudianakis Vangelis, Babusis Darius, Barauskas Ona, Birkus Gabriel, Butler Thomas, Byun Daniel, Chin Gregory, Doerffler Edward, Edwards Thomas E, Fenaux Martijn, Lee Rick, Lew Willard, Mish Michael R, Murakami Eisuke, Park Yeojin, Squires Neil H, Tirunagari Neeraj, Wang Ting, Whitcomb Mark, Xu Jie, Yang Huiling, Ye Hong, Zhang Lijun, Appleby Todd C, Feng Joy Y, Ray Adrian S, Cho Aesop, Kim Choung U
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1840-1847. doi: 10.1016/j.bmcl.2017.02.037. Epub 2017 Feb 20.
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.
制备了一系列2'-氟代C-核苷，并对其抗丙型肝炎病毒（HCV）活性进行了测试。其中，2'-氟-2'-C-甲基腺苷C-核苷（15）的三磷酸酯是NS5B聚合酶的有效且选择性抑制剂，对S282T耐药突变体仍保持活性。随后制备并评估了多种氨基磷酸酯前药，从而鉴定出具有良好药代动力学性质（包括在动物体内有效递送至肝脏）的1-氨基环丁烷-1-羧酸异丙酯变体（53）。
