4-Alkoxybenzamidines as new potent phospholipase A2 inhibitors.

A series of 4-alkoxybenzamidines was synthesized, varying the number of carbons of the alkyl chain, and their potency as phospholipase A(2) (PLA(2)) inhibitors was evaluated. The relationship between their capacity 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 tetradecyloxybenzamidines 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 effect in vitro on the carrageenan-induced rat paw oedema. These results show that 4-tetradecyloxybenzamidine will serve as an interesting tool to investigate the physiological role of mammalian-secreted PLA(2), both in vitro and in vivo.