Design, synthesis and antiviral evaluation of 2′-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor. (September 2015)

• Record Type: Journal Article
• Authors: Sizun, Gwenaëlle; Pierra, Claire; Peyronnet, Jérôme; Badaroux, Eric; Rabeson, Céline; Benzaria-Prad, Samira; Surleraux, Dominique; Loi, Anna Giulia; Musiu, Chiara; Liuzzi, Michel; Seifer, Maria; Standring, David; Sommadossi, Jean-Pierre; Gosselin, Gilles
• Is Part Of: Future medicinal chemistry. Volume 7:Number 13(2015)
• Page Start: 1675
• Page End: 1700
• Publication Date: 2015-09
• Subjects: 2′-C-methyl-branched guanosine derivatives -- HCV polymerase inhibitors -- pronucleotides; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc.15.96
• Languages: English
• ISSNs: 1756-8919

Abstract

Background: Ribonucleoside analogs possessing a β-methyl substituent at the 2′-position of thed -ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B.Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure–activity relationships of several phosphoramidate diester derivatives of 2′- C -methylguanosine (2′-MeG).Conclusion: The most promising compound, namely the O -[ S -(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O -[(HO) t BuSATE)]} N -benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.