4-ALKOXYBENZAMIDINES AS NEW POTENT PHOSPHOLIPASE A(2) INHIBITORS

A series of 4-alkoxybenzamidines was synthesized, varying the number o f carbons of the alkyl chain, and their potency as phospholipase A(2) (PLA(2)) inhibitors was evaluated. The relationship between their capa city to inhibit PLA(2) activity and their lipophilicity was examined. The optimum of the inhibitory effect against two extracellular PLA(2)s from rabbit platelets and bovine pancreas was observed with compounds bearing an alkyl chain of 12 and 14 carbons. These 4-dodecyl and tetr adecyloxybenzamidines inhibited bovine pancreatic and rabbit platelet lysate PLA(2)s with IC50 values of 3 mu M and 5-5.8 mu M, respectively . The mechanism of inhibition was of the competitive type. In addition , 4-tetradecyloxybenzamidine was shown to exert an anti-inflammatory e ffect in vitro on the carrageenan-induced rat paw oedema. These result s show that 4-tetradecyloxybenzamidine will serve as an interesting to ol to investigate the physiological role of mammalian-secreted PLA(2), both in vitro and in vivo.