3,4-Disubstituted isothiazoles: Novel potent inhibitors of VEGF receptors 1 and 2

Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib™ in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (>30 × 10−5 cm/min) across Caco-2 cell monolayer.

Graphical abstractNovel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed both good potency (27–41 nM) and 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1.Figure optionsDownload full-size imageDownload as PowerPoint slide