A new phospholipase A(2) inhibitor, unrelated to substrate analogues: Kinetic characterization of the inhibition of secretory phospholipases A(2) by PMS 832.

Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA(2)s of groups I or II, with IC50 in the micromolar range (Binisti et al., 1997). In this report we investigate the mechanism of inhibition of bovine and porcine pancreatic phospholipases A(2) (group I), and platelet lysate phospholipase A(2) (group II) by one of these compounds, 1-(4'-methoxybenzoyl)-2-n-tridecylpiperazine (PMS 832). We show that PMS 832 behaves as a reversible, competitive inhibitor, with K-i values of 4.1 +/- 1.2 and 1.5 +/- 0.4 mu M for porcine pancreatic phospholipase A(2) and platelet lysate phospholipase A(2), respectively. PMS 832 failed to inhibit platelet activation induced by several agonists and was also found to be inactive towards phospholipase C from Bacillus cereus, indicating a high specificity for phospholipase A(2) inactivation. Thus, PMS 832 and its derivatives could serve as interesting tools to investigate the role of extracellular phospholipases A(2) in inflammatory processes, and may be useful in the development of new anti-inflammatory agents. (C) 1997 Elsevier Science B.V.