Structure-activity relationships in platelet activating factor. 9. From PAF-antagonism to PLA2 inhibition

Many important mediators of inflammation result from the liberation of free arachidonic acid from phospholipid pools, which arise from the action of phospholipase A₂ (PLA2). Therefore the inhibition of this enzyme would be an important treatment in many inflammatory disease states. Starting from a series of compounds which are known as PAF-antagonists, we have synthesized new molecules. These new compounds inhibited various secretory PLA₂s, with IC₅₀'s in the μmol range. This allowed us to analyze the structure-activity relationships for PLA₂ inhibition. The results showed that inhibition of secretory PLA₂ depends on the length of the alkyl chain, with an optimum for 13 to 17 carbons, which is in agreement with X-ray crystallographic and nuclear magnetic resonance (NMR) studies on the active site of PLA₂s, and that a free nitrogen on the piperazine ring is required to ensure a good inhibitory potency.