title: Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
abstract: From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. mllinas@lav.boehringer-ingelheim.com
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.forename: Gordon
authors.initials: G
authors.lastname: Bolger
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faucher
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Ferland
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: Chantal
authors.initials: C
authors.lastname: Grand-Maître
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Nicole
authors.initials: N
authors.lastname: Lapeyre-Paquette
authors.forename: Francine
authors.initials: F
authors.lastname: Liard
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Manon
authors.initials: M
authors.lastname: Rhéaume
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D011392:Proline / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D006571:Heterocyclic Compounds; 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