title: Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease.
abstract: We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.
authors.affiliation: IDENIX, an MSD Company, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 MONTPELLIER Cedex 4, France. Electronic address: francois-rene.alexandre@merck.com.
authors.forename: François-René
authors.initials: FR
authors.lastname: Alexandre
authors.affiliation: IDENIX, an MSD Company, 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, an MSD Company, 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, an MSD Company, 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, an MSD Company, 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, an MSD Company, 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, an MSD Company, 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, an MSD Company, 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, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lallos
authors.affiliation: IDENIX, an MSD Company, 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, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: IDENIX, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Anna-Giulia
authors.initials: AG
authors.lastname: Loi
authors.affiliation: IDENIX, an MSD Company, 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, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Musiu
authors.affiliation: IDENIX, an MSD Company, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 MONTPELLIER Cedex 4, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Parsy
authors.affiliation: IDENIX, an MSD Company, 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, an MSD Company, 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, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: IDENIX, an MSD Company, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Standring
authors.affiliation: IDENIX, an MSD Company, 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: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006714:Homoserine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; 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: D000998:Antiviral Agents; D006714:Homoserine; 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
keywords: HCV NS3/4A protease inhibitors; Hepatitis C; Macrocycle; Synthesis and biological evaluation