title: Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency.
abstract: The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA. Electronic address: james_henderson@vrtx.com.
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: Darius
authors.initials: D
authors.lastname: Bilimoria
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Bubenik
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, 50 Northern Avenue, Boston, MA 02210, USA.
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: Evelyne
authors.initials: E
authors.lastname: Dietrich
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, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Ewing
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Falardeau
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Giroux
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Grey
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: Bingcan
authors.initials: B
authors.lastname: Liu
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Morris
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Nicolas
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Oswy Z
authors.initials: OZ
authors.lastname: Pereira
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Poisson
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: B
authors.initials: B
authors.lastname: Govinda Rao
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 Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Subajini
authors.initials: S
authors.lastname: Selliah
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shawgo
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Vaillancourt
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Yannopoulos
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, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Francoise
authors.initials: F
authors.lastname: Berlioz-Seux
authors.affiliation: Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Laval C
authors.initials: LC
authors.lastname: Chan
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, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Maxwell
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D005838:Genotype; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV; Hepatitis C virus; NS5A