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Bioorg Med Chem Lett. 2007 Mar 1;17(5):1369-75. Epub 2006 Dec 2.

ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2.

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Small Molecule Drug Discovery, Chemical Diversity, Inc., 11558 Sorrento Valley Road, San Diego, CA 92121, USA.


We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). 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.

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