title: Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase.
abstract: A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.
authors.affiliation: Chemical and Screening Sciences and Infectious Diseases Research, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nittoli
authors.forename: Kevin
authors.initials: K
authors.lastname: Curran
authors.forename: Shabana
authors.initials: S
authors.lastname: Insaf
authors.forename: Martin
authors.initials: M
authors.lastname: DiGrandi
authors.forename: Mark
authors.initials: M
authors.lastname: Orlowski
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Atul
authors.initials: A
authors.lastname: Agarwal
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.forename: Amar
authors.initials: A
authors.lastname: Prashad
authors.forename: M Brawner
authors.initials: MB
authors.lastname: Floyd
authors.forename: Bernard
authors.initials: B
authors.lastname: Johnson
authors.forename: Alan
authors.initials: A
authors.lastname: Sutherland
authors.forename: Karen
authors.initials: K
authors.lastname: Wheless
authors.forename: Boris
authors.initials: B
authors.lastname: Feld
authors.forename: John
authors.initials: J
authors.lastname: O'Connell
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bloom
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D012093:Replicon; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase