Abstract
Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.
MeSH terms
-
Administration, Oral
-
Aminopyridines / chemical synthesis*
-
Aminopyridines / pharmacokinetics
-
Aminopyridines / pharmacology
-
Angiogenesis Inhibitors / chemical synthesis*
-
Angiogenesis Inhibitors / pharmacokinetics
-
Angiogenesis Inhibitors / pharmacology
-
Animals
-
Binding Sites
-
Cell Proliferation
-
Endothelial Cells / cytology
-
Endothelial Cells / drug effects
-
Endothelium, Vascular / cytology
-
Humans
-
In Vitro Techniques
-
Macaca fascicularis
-
Mice
-
Mice, Nude
-
Models, Molecular
-
Rats
-
Structure-Activity Relationship
-
Thiazoles / chemical synthesis*
-
Thiazoles / pharmacokinetics
-
Thiazoles / pharmacology
-
Umbilical Veins / cytology
-
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
-
Vascular Endothelial Growth Factor Receptor-2 / chemistry
-
Xenograft Model Antitumor Assays
Substances
-
Aminopyridines
-
Angiogenesis Inhibitors
-
N-cyclopropyl-2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamide
-
Thiazoles
-
Vascular Endothelial Growth Factor Receptor-2