title: Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.
abstract: The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France. Electronic address: claire.pierra-rouviere@merck.com.
authors: Claire
authors: C
authors: Pierra Rouvière
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Agnès
authors: A
authors: Amador
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Eric
authors: E
authors: Badaroux
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Thierry
authors: T
authors: Convard
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Daniel
authors: D
authors: Da Costa
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: David
authors: D
authors: Dukhan
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Ludovic
authors: L
authors: Griffe
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Jean-François
authors: JF
authors: Griffon
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors: Massimiliano
authors: M
authors: LaColla
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Frédéric
authors: F
authors: Leroy
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors: Michel
authors: M
authors: Liuzzi
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors: Anna Giulia
authors: AG
authors: Loi
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors: Joe
authors: J
authors: McCarville
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors: Valeria
authors: V
authors: Mascia
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Julien
authors: J
authors: Milhau
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors: Loredana
authors: L
authors: Onidi
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Jean-Laurent
authors: JL
authors: Paparin
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Rachid
authors: R
authors: Rahali
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Laboratorio Cooperativo Idenix-Università di Cagliari, Zona Industriale di Macchiareddu, Sesta strada ovest, 09010 Uta (Cagliari), Italy.
authors: Efisio
authors: E
authors: Sais
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors: Maria
authors: M
authors: Seifer
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Dominique
authors: D
authors: Surleraux
authors: Idenix Employee of the Former Idenix Pharmaceuticals Company, One Kendall Square, Ste B14104, Cambridge, MA 02139-1573, USA.
authors: David
authors: D
authors: Standring
authors: Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP 50001, 34189 Montpellier Cedex 4, France.
authors: Cyril
authors: C
authors: Dousson
mesh_terms: D000495:Allosteric Site; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Allosteric inhibitors; Amide bioisostere; Direct-acting antivirals; Hepatitis C virus; NS5B non-nucleoside inhibitors; Polymerase inhibitors