Novel inhibitors of VEGF receptors-1 and -2 based on azole-5-carboxamide templates

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 (IC50 < 100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade) and ZD6474 (Vandetanib™). High permeability of active compounds across the Caco-2 cell monolayer (>40 × 10−5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.

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