INHIBITOR OF PHOSPHOLIPASE A(2) BLOCKS EICOSANOID AND PLATELET-ACTIVATING-FACTOR BIOSYNTHESIS AND HAS TOPICAL ANTIINFLAMMATORY ACTIVITY

The effect of a phospholipase A(2) (PLA(2)) inhibitor on leukotriene, prostaglandin and platelet activating factor (PAF) biosynthesis in iso lated cells and in vivo was determined. BMS-181162, rboxyphenyl)-3,7-d imethyl-9(2'',6''-trimethyl-1''- cyclohexenyl),2Z,4E,GE,8E-nonatetraen oic acid], reversibly inhibited the 14-kdalton PLA(2) purified from hu man synovial fluid with an IC50 of 8 mu m. In A23187-stimulated human polymor-phonuclear leukocytes (PMNs), BMS-181162 blocked arachidonic a cid release with an IC50 of 10 mu m. Leukotriene B-4 and PAF biosynthe sis in these cells was also inhibited. In a phorbol ester-induced chro nic mouse skin inflammation model, topically applied BMS-181162 marked ly lowered the tissue levels of leukotriene B-4 and prostaglandin E(2) and dose-dependently inhibited leukocyte infiltration (ED(50) = 180 m u g per ear). BMS-181162 is an inhibitor of PLA(2) and may prove to be a useful tool in the delineation of the role of PLA(2) in the inflamm atory process.