title: Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
abstract: Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).
authors.affiliation: IDENIX Pharmaceuticals, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France. Electronic address: parsy.christophe@idenix.com.
authors.forename: Christophe
authors.initials: C
authors.lastname: Parsy
authors.affiliation: IDENIX Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lallos
authors.affiliation: IDENIX Pharmaceuticals, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Leroy
authors.affiliation: IDENIX Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: IDENIX Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Anna-Giulia
authors.initials: AG
authors.lastname: Loi
authors.affiliation: IDENIX Pharmaceuticals, 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 Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Musiu
authors.affiliation: IDENIX Pharmaceuticals, 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 Pharmaceuticals, 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 Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: IDENIX Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Standring
authors.affiliation: IDENIX Pharmaceuticals, 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: D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D001384:Azetidines; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; 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; C082735:azetidine
keywords: HCV NS3/4A protease inhibitors; Hepatitis C; Macrocycle