title: Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors.
abstract: The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Giroux
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jinwang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: T Jagadeeswar
authors.initials: TJ
authors.lastname: Reddy
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Morris
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cottrell
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cadilhac
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Henderson
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nicolas
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Darius
authors.initials: D
authors.lastname: Bilimoria
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Denis
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Nigel
authors.initials: N
authors.lastname: Ewing
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shawgo
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Lucille
authors.initials: L
authors.lastname: L'Heureux
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Subajini
authors.initials: S
authors.lastname: Selliah
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Laval
authors.initials: L
authors.lastname: Chan
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Francoise
authors.initials: F
authors.lastname: Berlioz-Seux
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Namchuk
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Maxwell
keywords: HCV; NS5A; thienoimidazoles