Differential Inhibition of Group IVA and Group VIA Phospholipases A2by 2-Oxoamides

Abstract

Inhibitors of the Group IVA phospholipase A₂ (GIVA cPLA₂) and GVIA iPLA₂ are useful tools for defining the roles of these enzymes in cellular signaling and inflammation. We have developed inhibitors of GVIA iPLA₂ building upon the 2-oxoamide backbone that are uncharged, containing ester groups. Although the most potent inhibitors of GVIA iPLA₂ also inhibited GIVA cPLA₂, there were three 2-oxoamide compounds that selectively and weakly inhibited GVIA iPLA₂. We further show that several potent 2-oxoamide inhibitors of GIVA cPLA₂ containing free carboxylic groups (Kokotos et al. J. Med. Chem. 2002, 45, 2891−2893) do not inhibit GVIA iPLA₂ and are, therefore, selective GIVA cPLA₂ inhibitors.