title: Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.
abstract: The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.
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 H7V 4A7, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Poisson
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ardzinski
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
authors.forename: Darius
authors.initials: D
authors.lastname: Bilimoria
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
authors.forename: Laval
authors.initials: L
authors.lastname: Chan
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kishan
authors.initials: K
authors.lastname: Chandupatla
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 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: Philip N
authors.initials: PN
authors.lastname: Collier
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
authors.forename: Sanjoy Kumar
authors.initials: SK
authors.lastname: Das
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 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: Warren
authors.initials: W
authors.lastname: Dorsch
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David
authors.initials: D
authors.lastname: Lauffer
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
authors.forename: Lucille
authors.initials: L
authors.lastname: L'Heureux
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: Brian S
authors.initials: BS
authors.lastname: Luisi
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: Suganthi
authors.initials: S
authors.lastname: Nanthakumar
authors.affiliation: Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 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 H7V 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: 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 (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Yannopoulos
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003511:Cyclohexanols; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C000592793:lomibuvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase