title: Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.
abstract: Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound2, a molecule with comparable potency and an improved physicochemical profile relative to1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships,in vitroADME characterization, andin vivoevaluation of this novel series are discussed.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Warren
authors.initials: W
authors.lastname: Dorsch
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lauffer
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Darius
authors.initials: D
authors.lastname: Bilimoria
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Court
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
authors.forename: Sanjoy Kumar
authors.initials: SK
authors.lastname: Das
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Denis
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Suganthini
authors.initials: S
authors.lastname: Nanthakumar
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Nicolas
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: B Govinda
authors.initials: BG
authors.lastname: Rao
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Ronkin
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
authors.forename: Subajini
authors.initials: S
authors.lastname: Selliah
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shawgo
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stearns
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Waal
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
keywords: Lomibuvir; NS5B; antiviral activity; hepatitis C; non-nucleoside; polymerase