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 (IC50 < 100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib™). High permeability of active compounds across the Caco-2 cell monolayer (>30 × 10−5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.

Graphical abstractWe 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. Most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in both in vitro and cell-based assays (IC50 < 100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib™). High permeability of the active compounds across Caco-2 cell monolayer (>30 × 10−5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.Figure optionsDownload full-size imageDownload as PowerPoint slide