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Bioorg Med Chem Lett. 2017 Apr 15;27(8):1840-1847. doi: 10.1016/j.bmcl.2017.02.037. Epub 2017 Feb 20.

Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.

Author information

1
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: tkirschberg@gilead.com.
2
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
3
Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.

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.

KEYWORDS:

Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase

PMID:
28274633
DOI:
10.1016/j.bmcl.2017.02.037
[Indexed for MEDLINE]

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