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

Article Details

Citation

Kiselyov AS, Piatnitski EL, Samet AV, Kisliy VP, Semenov VV

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

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

PubMed ID
17188873 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VatalanibVascular endothelial growth factor receptor 1IC 50 (nM)54N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 2IC 50 (nM)21N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 2IC 50 (nM)140N/AN/ADetails