title: The discovery of benzanilides as c-Met receptor tyrosine kinase inhibitors by a directed screening approach.
abstract: A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12.
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Joanne V
authors.initials: JV
authors.lastname: Allen
authors.forename: Catherine
authors.initials: C
authors.lastname: Bardelle
authors.forename: Kevin
authors.initials: K
authors.lastname: Blades
authors.forename: Dave
authors.initials: D
authors.lastname: Buttar
authors.forename: Louise
authors.initials: L
authors.lastname: Chapman
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Dossetter
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Garner
authors.forename: Alan
authors.initials: A
authors.lastname: Girdwood
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Brian
authors.initials: B
authors.lastname: Law
authors.forename: John
authors.initials: J
authors.lastname: Major
authors.forename: Helen
authors.initials: H
authors.lastname: Plant
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Slater
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D047428:Protein Kinase Inhibitors; C034595:benzanilide; D019859:Proto-Oncogene Proteins c-met