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 new class of inhibitors of secretory phospholipase A(2) from human polymorphonuclear leucocytes (h-PMN PLA(2)). Among the more than 30 compounds synthesized, the most potent inhibitors (IC50 0.6-10 mu M) were found in the series of 2,4-disubstituted phenyl analogues of a. Compound 1a was selected for evaluation of its biological profile. This substance potently inhibited secretory PLA(2)s from several sources other than human PMNs, with a clear preference for group II over group I PLA(2), whereas human cytosolic PLA(2) and phospholipase C were not significantly 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 inhibited at concentrations compatible with inhibition of PLA(2) as an underlying mechanism. In animal models in vivo (carragheenan oedema, adjuvant arthritis, pertussis pleurisy) 1a showed antiinflammatory activity, although the effect was rather weak compared with standard reference compounds.