Design, Synthesis, and Biological Evaluation of 3‑(1-Aryl‑1<i>H</i>‑indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Abstract

This article describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A₂α (cPLA₂α, a group IVA phospholipase A₂) inhibitors. A screening-hit compound from our library, (<i>E</i>)-3-{4-[(4-chlorophenyl)­thio]-3-nitrophenyl}­acrylic acid (<b>5</b>), was used to design a class of 3-(1-aryl-1<i>H</i>-indol-5-yl)­propanoic acids as new small molecule inhibitors. The resultant structure–activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(<i>p</i>-<i>O</i>-substituted)­phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA₂α. Optimization of the <i>p</i>-substituents on the N1 phenyl group led to the discovery of <b>56n</b> (ASB14780), which was shown to be a potent inhibitor of cPLA₂α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models