Design and Synthesis of l-Indol-l-yl-propan-2-ones as Inhibitors of Human Cytosolic Phospholipase A_2 alpha

摘要

The synthesis and structure-activity relationship study of a series of l-indol-l-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 l-[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.