title: Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.
abstract: Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France. Electronic address: christophe.parsy@merck.com.
authors.forename: Christophe C
authors.initials: CC
authors.lastname: Parsy
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: François-René
authors.initials: FR
authors.lastname: Alexandre
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bidau
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bonnaterre
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Brandt
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillet
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cappelle
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chaves
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Convard
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Derock
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Gloux
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Griffon
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Lallos
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Leroy
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Anna-Giulia
authors.initials: AG
authors.lastname: Loi
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Moulat
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Musiu
authors.initials: M
authors.lastname: Chiara
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Houcine
authors.initials: H
authors.lastname: Rahali
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Roques
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Rosinovsky
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Savin
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Standring
authors.affiliation: IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Surleraux
mesh_terms: D000818:Animals; D055808:Drug Discovery; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C574703:IDX320; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus
keywords: HCV NS3/4A protease inhibitors; Hepatitis C; Macrocycle