Design and synthesis of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones as inhibitors of human cytosolic phospholipase A2alpha.

A series of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones was synthesized and assessed for the ability to inhibit cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Several of these compounds were found to be active in both a cell based assay and an isolated enzyme assay. The most potent inhibitor was the thiazolidine-2,4-dione substituted derivative 35. With IC(50)-values of 0.7 muM and 7.3 muM in the cellular and isolated enzyme assay, respectively, it possesses similar inhibitory potency as the known cPLA(2)alpha inhibitor arachidonyltrifluoromethyl ketone (AACOCF(3)). Structure-activity relationship studies revealed that the evaluated isobenzofuran-1-ones seem to exert their cellular activities not only by a direct interaction with the enzyme but also by other as yet unknown mechanisms.