[摘要]：In this study we report on the design, synthesis, and biol. evaluation of pyrrol-2-one I (X = C:O, Y = CH2) (II) to be a highly potent VEGF-R2/3 inhibitor with IC50 of 31/37 nM. The novel 3,4-diaryl-2H-pyrrol-2-ones were designed on the basis of the modeled binding mode of the corresponding 1H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor I (X = Y= C:O) (III) indicating two H-bond ligand-protein interactions in the (IV). Flexible synthetic routes to 3,4-diaryl-2H-pyrrol-2-ones and structure-activity relationships for the compds. in a panel of 24 therapeutically relevant protein kinases (IC50 values) are presented. Accordingly to the in vitro data, compds. II and III were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas IV was detd. to be significantly less active. Hence, the pyrrol-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.
