Inhibitor of phospholipase A₂ blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity

The effect of a phospholipase A₂ (PLA₂) inhibitor on leukotriene, prostaglandin and platelet activating factor (PAF) biosynthesis in isolated cells and in vivo was determined. BMS-181162, [4(3'-carboxyphenyl)-3,7- dimethyl-9(2'',6'',6''-trimethyl-1''-cyclohexenyl),2Z,4E,6E,8E-nonatetraenoic acid], reversibly inhibited the 14-kdalton PLA₂ purified from human synovial fluid with an IC₅₀ of 8 μm. In A23187-stimulated human polymorphonuclear leukocytes (PMNs), BMS-181162 blocked arachidonic acid release with an IC₅₀ of 10 μm. Leukotriene B₄ and PAF biosynthesis in these cells was also inhibited. In a phorbol ester-induced chronic mouse skin inflammation model, topically applied BMS-181162 markedly lowered the tissue levels of leukotriene B₄ and prostaglandin E₂ and dose-dependently inhibited leukocyte infiltration (ED₅₀ = 180 μg per ear). BMS-181162 is an inhibitor of PLA₂ and may prove to be a useful tool in the delineation of the role of PLA₂ in the inflammatory process.