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.
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.
Renhowe
Paul A
PA
Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608-2419, USA. paul.renhowe@novartis.com
Pecchi
Sabina
S
Shafer
Cynthia M
CM
Machajewski
Timothy D
TD
Jazan
Elisa M
EM
Taylor
Clarke
C
Antonios-McCrea
William
W
McBride
Christopher M
CM
Frazier
Kelly
K
Wiesmann
Marion
M
Lapointe
Gena R
GR
Feucht
Paul H
PH
Warne
Robert L
RL
Heise
Carla C
CC
Menezes
Daniel
D
Aardalen
Kimberly
K
Ye
Helen
H
He
Molly
M
Le
Vincent
V
Vora
Jayesh
J
Jansen
Johanna M
JM
Wernette-Hammond
Mary Ellen
ME
Harris
Alex L
AL
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
D047428:Protein Kinase Inhibitors; D015363:Quinolones; D020794:Receptor Protein-Tyrosine Kinases