Chapter 17. Recent Advances in the Design and Evaluation of Inhibitors of Phospholipase A2

Publisher Summary This chapter discusses the recent advances in the design and evaluation of inhibitors of phospholipase A 2 (PLA 2 ). PLA 2 refers to a large class of acylhydrolytic enzymes that specifically act at the sn-2 position of phospholipid substrate. Substrate sources are derived from two broad categories: 1) synthetic PL or 2) natural “membrane” lipid forms. The use of PLA 2 administration as the initiating inflammatory insult are the most documented and well characterized models in terms of evaluating the proinflammatory activity of PLA 2 . The activity of PLA 2 is greatly enhanced when the substrate is above its critical micelle concentration (CMC). The importance of comparing inhibitor activity against the same enzyme can be illustrated with manoalide. Its IC 50 value for inhibition of PLA 2 hydrolysis has been measured against a number of enzymes and varies over almost three log units. The inhibitory effects of these retinoids on the release and metabolism of AA from rat peritoneal macrophages challenged with A23187, zymosan, and 12-O-tetradecanoate phorbol-13-acetate (TPA) have also been studied. Several other natural products have also been reported to inhibit PLA 2 . Gossypol, a male non-steroidal antifertility agent, has been shown, at 100 μM, to completely inhibit intact human spermatozoa PLA 2 hydrolysis of monolayers of phosphatidylglycerol. A three-dimensional study of the bovine pancreatic PLA 2 X-ray structure, with the goal of identifying novel compounds that fit both sterically and electronically into the active site, has resulted in the identification of a series of potent in vitro inhibitors. Another study of the same X-ray structure has resulted in the synthesis of long chain alkylamine inhibitors. Although there has been considerable activity in this field over the last decade, much work remains before a clinical candidate can emerge.