STRUCTURE-ACTIVITY-RELATIONSHIPS IN PLATELET-ACTIVATING-FACTOR .9. FROM PAF-ANTAGONISM TO PLA(2) INHIBITION

Many important mediators of inflammation result from the liberation of free arachidonic acid from phospholipid pools, which arise from the a ction of phospholipase A(2) (PLA(2)). Therefore the inhibition of this enzyme would be an important treatment in many inflammatory disease s lates. Starting from a series of compounds which are known as PAF-anta gonists, we have synthesized new molecules. These new compounds inhibi ted various secretory PLA(2)s, with IC50's in the mu mol range. This a llowed us to analyze the structure-activity relationships for PLA(2) i nhibition. The results showed that inhibition of secretory PLA(2) depe nds on the length of the alkyl chain, with an optimum for 13 to 17 car bons, which is in agreement with X-ray crystallographic and nuclear ma gnetic resonance (NMR) studies on the active site of PLA(2)s, and that a free nitrogen on the piperazine ring is required to ensure a good i nhibitory potency.