title: Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.
abstract: Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: kyle.parcella@bms.com.
authors.forename: Kyle
authors.initials: K
authors.lastname: Parcella
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nickel
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.affiliation: Bristol-Myers Squibb, Research and Development, PO Box 4000, Princeton, NJ 08540, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.affiliation: Bristol-Myers Squibb, Research and Development, PO Box 4000, Princeton, NJ 08540, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Wan
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Ying-Kai
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Allosteric inhibitors; Hepatitis C virus (HCV); NS5B polymerase; Primer grip