A new phospholipase A2 inhibitor, unrelated to substrate analogues: kinetic characterization of the inhibition of secretory phospholipases A2 by PMS 832.

Abstract

Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA₂s 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 A₂ (group I), and platelet lysate phospholipase A₂ (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 μM for porcine pancreatic phospholipase A₂ and platelet lysate phospholipase A₂, 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 A₂ inactivation. Thus, PMS 832 and its derivatives could serve as interesting tools to investigate the role of extracellular phospholipases A₂ in inflammatory processes, and may be useful in the development of new anti-inflammatory agents.