The Group IVA cytosolic phospholipase A2 (GIVA cPLA2) is a key provider of substrates for the productionof eicosanoids and platelet-activating factor. We explored the structure−activity relationship of 2-oxoamide-based compounds and GIVA cPLA2 inhibition. The most potent inhibitors are derived from δ- and γ-aminoacid-based 2-oxoamides. The optimal side-chain moiety is a short nonpolar aliphatic chain. All of the newlydeveloped 2-oxoamides as well as those previously described have now been tested with the human GroupV secreted PLA2 (GV sPLA2) and the human Group VIA calcium-independent PLA2 (GVIA iPLA2). Onlyone 2-oxoamide compound had appreciable inhibition of GV sPLA2, and none of the potent GIVA cPLA2inhibitors inhibited either GV sPLA2 or GVIA iPLA2. Two of these specific GIVA cPLA2 inhibitors werealso found to have potent therapeutic effects in animal models of pain and inflammation at dosages wellbelow the control nonsteroidal anti-inflammatory drugs.
