4-Alkoxybenzamidines as new potent phospholipase A2 inhibitors

Article abstract of DOI:10.1016/0006-2952(95)02172-8

A series of 4-alkoxybenzamidines was synthesized, varying the number of carbons of the alkyl chain, and their potency as phospholipase A₂ (PLA₂) inhibitors was evaluated. The relationship between their capacity to inhibit PLA₂ activity and their lipophilicity was examined. The optimum of the inhibitory effect against two extracellular PLA₂s 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 PLA₂s with IC₅₀ values of 3 μM and 5-5.8 μM, respectively. The mechanism of inhibition was of the competitive type. In addition, 4-tetradecyloxybenzamidine was shown to exert an anti-inflammatory effect in vivo 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 PLA₂, both in vitro and in vivo.