Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties. Issue 8 (15th April 2017)

• Record Type: Journal Article
• Authors: 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.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 8(2017)
• Page Start: 1840
• Page End: 1847
• Publication Date: 2017-04-15
• Subjects: Hepatitis C -- Antiviral -- C-nucleoside -- NS5B polymerase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.02.037
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.