Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template.
We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole 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)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Kiselyov
Alexander S
AS
Small Molecule Drug Discovery, Chemical Diversity, Inc, 11558 Sorrento Valley Road, San Diego, CA 92121, USA. ask@chemdiv.com
Semenova
Marina
M
Semenov
Victor V
VV
Milligan
Daniel
D
D018938:Caco-2 Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011725:Pyridines / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011725:Pyridines; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2