Design and Synthesis of 1-Indol-1-yl-propan-2-ones as Inhibitors of Human Cytosolic Phospholipase A2α

The synthesis and structure−activity relationship study of a series of 1-indol-1-yl-3-phenoxypropan-2-one inhibitors of cytosolic phospholipase A2α (cPLA2α) are described. The compounds were evaluated in a vesicle assay with isolated cPLA2α 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 IC50 value of 4.3 nM in this assay, it is one of the most potent in vitro cPLA2α inhibitors known today.