title: Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores.
abstract: Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.
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: Francois
authors.initials: F
authors.lastname: Denis
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 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 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 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 Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
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: 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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV; Hepatitis C; NS5A