title: Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4-arylproline analogs.
abstract: In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec, Canada H7S 2G5. RESGeneral.lav@boehringer-ingelheim.com
authors.forename: François
authors.initials: F
authors.lastname: Bilodeau
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.forename: Punit K
authors.initials: PK
authors.lastname: Bhardwaj
authors.forename: Josée
authors.initials: J
authors.lastname: Bordeleau
authors.forename: Pat
authors.initials: P
authors.lastname: Forgione
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Elise
authors.initials: E
authors.lastname: Ghiro
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Eric S
authors.initials: ES
authors.lastname: Jolicoeur
authors.forename: Mélissa
authors.initials: M
authors.lastname: Leblanc
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
authors.forename: Julie
authors.initials: J
authors.lastname: Naud
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: Peter W
authors.initials: PW
authors.lastname: White
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D015195:Drug Design; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000502:physiology; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011392:Proline; D011480:Protease 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