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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}-4 H -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. Modeling predicted some derivatives to display greater GIIAPLA 2  affinities than did  C1 , and such predictions were confirmed by  in vitro  PLA 2  enzymatic tests. Compound  C8 , endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA 2  inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE 2  secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio.  C8  is therefore a potential candidate for anti-inflammatory therapy in joints.

Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion