Design and synthesis of 1-indol-1-yl-propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha.

The synthesis and structure-activity relationship study of a series of 1-indol-1-yl-3-phenoxypropan-2-one inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) are described. The compounds were evaluated in a vesicle assay with isolated cPLA(2)alpha and in cellular assays with intact human platelets. Systematic variation led to 3-methylhydrogen 1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate (57), which revealed the highest activity against the isolated enzyme. With an IC(50) value of 4.3 nM in this assay, it is one of the most potent in vitro cPLA(2)alpha inhibitors known today.