Design of group IIA secreted/synovial phospholipase A(2) inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2) secretion.

Group IIA secreted/synovial phospholipase A(2) (GIIAPLA(2)) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2) (PGE(2)), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2) enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2), along with their chemical synthesis and results from PLA(2) inhibition tests.

Inhibition of secretory phospholipase A2. 2-Synthesis and structure-activity relationship studies of 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one (PMS1062) derivatives specific for group II enzyme.

We have recently reported the discovery of a series of specific inhibitors of human group IIA phospholipase A(2) (hGIIA PLA(2)) to display promising in vitro and in vivo properties. Here we describe the influence of different structural modifications on the specificity and potency against hGIIA PLA(2) versus porcine group IB PLA(2). The SAR results, as well as the logP and pK(a) values of oxadiazolone determined in this work, provide important information towards the comprehension of the mode of action of this kind of compounds.