title: Design, synthesis and antiviral evaluation of 2'-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor.
abstract: BACKGROUND
  Ribonucleoside analogs possessing a β-methyl substituent at the 2'-position of the d-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).
  
  
  CONCLUSIONS
  The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} 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.
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Sizun
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pierra
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Peyronnet
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Badaroux
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Rabeson
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Benzaria-Prad
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Surleraux
authors.affiliation: Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors.forename: Anna Giulia
authors.initials: AG
authors.lastname: Loi
authors.affiliation: Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Musiu
authors.affiliation: Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors.forename: David
authors.initials: D
authors.lastname: Standring
authors.affiliation: Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Sommadossi
authors.affiliation: Idenix SARL (an MSD Company since August 2014), Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsiere, B.P. 50001, 34189 Montpellier, Cedex 4, France.|Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, case courrier 1705, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gosselin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D055808:Drug Discovery; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; C557801:IDX184; D006157:Guanosine Monophosphate
keywords: 2′-C-methyl-branched guanosine derivatives; HCV polymerase inhibitors; pronucleotides