Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups

A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere—a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.

Graphical abstractA novel series of analogues of malonamides 1, previously known as dual c-Met/VEGFR2 inhibitors, in which one of the amide bonds was substituted by an amide isostere such as a trifluoroethylamine unit (regioisomers 2 and 3) was prepared and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Some of these analogs (regioisomers 3) were shown to be potent and selective inhibitors of VEGFR2 in the enzymatic assay and displayed significant effect against VEGFR-dependent angiogenic activity in cells.Figure optionsDownload full-size imageDownload as PowerPoint slide