A NEW CLASS OF INHIBITORS OF SECRETORY PHOSPHOLIPASE A(2) - ENOLIZED 1,3-DIOXANE-4,6-DIONE-5-CARBOXAMIDES

Enolized 1,3-dioxane-4,6-dione-5-carboxamides a were identified as a n ew class of inhibitors of secretory phospholipase A(2) from human poly morphonuclear leucocytes (h-PMN PLA(2)). Among the more than 30 compou nds synthesized, the most potent inhibitors (IC50 0.6-10 mu M) were fo und in the series of 2,4-disubstituted phenyl analogues of a. Compound 1a was selected for evaluation of its biological profile. This substa nce potently inhibited secretory PLA(2)s from several sources other th an human PMNs, with a clear preference for group II over group I PLA(2 ), whereas human cytosolic PLA(2) and phospholipase C were not signifi cantly affected. Inhibition of h-PMN PLA(2) was calcium-dependent. In intact mammalian cells stimulated in vitro, the release of arachidonic acid and the generation of prostaglandins and leukotrienes were inhib ited at concentrations compatible with inhibition of PLA(2) as an unde rlying mechanism. In animal models in vivo (carragheenan oedema, adjuv ant arthritis, pertussis pleurisy) 1a showed antiinflammatory activity , although the effect was rather weak compared with standard reference compounds.