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.