title: Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase.
abstract: A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
authors.affiliation: GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Maynard
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Byron
authors.initials: B
authors.lastname: Ellis
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Kahler
authors.forename: Cecilia
authors.initials: C
authors.lastname: Koble
authors.forename: Anna
authors.initials: A
authors.lastname: Leivers
authors.forename: Martin R
authors.initials: MR
authors.lastname: Leivers
authors.forename: Amanda
authors.initials: A
authors.lastname: Mathis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Pouliot
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Roberts
authors.forename: Vicente
authors.initials: V
authors.lastname: Samano
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Schmidt
authors.forename: Gary K
authors.initials: GK
authors.lastname: Smith
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Turner
authors.forename: Christian
authors.initials: C
authors.lastname: Voitenleitner
authors.forename: Jill T
authors.initials: JT
authors.lastname: Walker
authors.forename: Greg
authors.initials: G
authors.lastname: Waitt
authors.forename: Jason
authors.initials: J
authors.lastname: Weatherhead
authors.forename: Kurt
authors.initials: K
authors.lastname: Weaver
authors.forename: Shawn
authors.initials: S
authors.lastname: Williams
authors.forename: Lois
authors.initials: L
authors.lastname: Wright
authors.forename: Zhiping Z
authors.initials: ZZ
authors.lastname: Xiong
authors.forename: David
authors.initials: D
authors.lastname: Haigh
authors.forename: J Brad
authors.initials: JB
authors.lastname: Shotwell
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry*; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase