title: Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.
abstract: The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
authors.affiliation: Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608-2419, USA. paul.renhowe@novartis.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Renhowe
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Shafer
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Machajewski
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Jazan
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.forename: William
authors.initials: W
authors.lastname: Antonios-McCrea
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McBride
authors.forename: Kelly
authors.initials: K
authors.lastname: Frazier
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Gena R
authors.initials: GR
authors.lastname: Lapointe
authors.forename: Paul H
authors.initials: PH
authors.lastname: Feucht
authors.forename: Robert L
authors.initials: RL
authors.lastname: Warne
authors.forename: Carla C
authors.initials: CC
authors.lastname: Heise
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes
authors.forename: Kimberly
authors.initials: K
authors.lastname: Aardalen
authors.forename: Helen
authors.initials: H
authors.lastname: Ye
authors.forename: Molly
authors.initials: M
authors.lastname: He
authors.forename: Vincent
authors.initials: V
authors.lastname: Le
authors.forename: Jayesh
authors.initials: J
authors.lastname: Vora
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Jansen
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Wernette-Hammond
authors.forename: Alex L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D015363:Quinolones; D020794:Receptor Protein-Tyrosine Kinases