A new class of inhibitors of secretory phospholipase A2: enolized 1,3-dioxane-4,6-dione-5-carboxamides

Article abstract of DOI:10.1016/0223-5234(94)90026-4

Enolized 1,3-dioxane-4,6-dione-5-carboxamides a were identified as a new class of inhibitors of secretory phospholipase A₂ from human polymorphonuclear leucocytes (h-PMN PLA₂).Among the more than 30 compounds synthesized, the most potent inhibitors (IC50 0.6-10 μM) 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 PLA₂s from several sources other than human PMNs, with a clear preference for group II over group I PLA₂, whereas humancytosolic PLA₂ and phospholipase C were not significantly affected.Inhibition of h-PMN PLA₂ 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 PLA₂ 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. secretory human PMN phospholipase A₂ / enolized 1,3-dioxane-4,6-dione-5-carboxamide inhibitors / cellular eicosanoid synthesis / in vivo antiinflammatory activity / molecular modelling / structure-activity relationship