Abstract
We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases VEGFR-2 and -1. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib(trade)) and ZD6474 (Vandetanib(trade mark)). High permeability of active compounds across the Caco-2 cell monolayer (>40 x 10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
MeSH terms
-
Adenosine Triphosphate / chemistry
-
Amides / chemistry*
-
Azoles / chemistry*
-
Azoles / pharmacology
-
Binding, Competitive
-
Caco-2 Cells
-
Cell Line, Tumor
-
Chemistry, Pharmaceutical / methods*
-
Drug Screening Assays, Antitumor*
-
Humans
-
Inhibitory Concentration 50
-
Models, Chemical
-
Phthalazines / pharmacology
-
Piperidines / pharmacology
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Pyridines / pharmacology
-
Quinazolines / pharmacology
-
Vascular Endothelial Growth Factor Receptor-1 / metabolism*
-
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
-
Amides
-
Azoles
-
Phthalazines
-
Piperidines
-
Protein Kinase Inhibitors
-
Pyridines
-
Quinazolines
-
vatalanib
-
Adenosine Triphosphate
-
Vascular Endothelial Growth Factor Receptor-1
-
Vascular Endothelial Growth Factor Receptor-2
-
vandetanib