Structure-activity relationship of 2-oxoamide inhibition of group IVA cytosolic phospholipase A2 and group v secreted phospholipase A2

The Group IVA cytosolic phospholipase A(2) (GIVA cPLA(2)) is a key provider of substrates for the production of eicosanoids and platelet-activating factor. We explored the structure-activity relationship of 2-oxoamide-based compounds and GIVA cPLA(2) inhibition. The most potent inhibitors are derived from delta- and gamma-amino acid-based 2-oxoamides. The optimal side-chain moiety is a short nonpolar aliphatic chain. All of the newly developed 2-oxoamides as well as those previously described have now been tested with the human Group V secreted PLA(2) (GV sPLA(2)) and the human Group VIA calcium-independent PLA(2) (GVIA iPLA(2)). Only one 2-oxoamide compound had appreciable inhibition of GV sPLA(2), and none of the potent GIVA cPLA(2) inhibitors inhibited either GV sPLA(2) or GVIA iPLA(2). Two of these specific GIVA cPLA(2) inhibitors were also found to have potent therapeutic effects in animal models of pain and inflammation at dosages well below the control nonsteroidal anti-inflammatory drugs.