Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2.

Abstract Phospholipase A 2 (PLA 2) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA 2 inhibitors developed to target each one of the four major types of human PLA 2 (cytosolic cPLA 2 , calcium-independent iPLA 2, secreted sPLA 2, and lipoprotein-associated LpPLA 2). We discuss recent applications of inhibitors to understand the role of each PLA 2 type and their therapeutic potential. Potent and selective PLA 2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA 2 inhibitors are excellent tools to unveil the role that each PLA 2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA 2 inhibitors as new agents to treat inflammatory diseases. [ABSTRACT FROM AUTHOR]