Pure and Applied Chemistry

Abstract: Phospholipases A₂ (PLA₂s) are enzymes that are capable of catalyzing the hydrolysis of the sn-2 ester bond of glycerophospholipids, releasing free fatty acids, including arachidonic acid (AA), and lysophospholipids. Both products are precursor signaling molecules involved in inflammation. Among the various PLA₂s, cytosolic GIVA cPLA₂ is considered a major target for inflammatory diseases, while secreted GIIA sPLA₂ is involved in cardiovascular diseases. We have developed lipophilic 2-oxoamides based on (S)-γ- or δ‑amino acids as potent and selective inhibitors of GIVA cPLA₂, which present interesting in vivo anti-inflammatory activity. 2-Oxoamides based on natural α-amino acids are selective inhibitors of GIIA sPLA₂. The mode of binding of 2-oxoamides with either GIVA cPLA₂ or GIIA sPLA₂ has been studied by various techniques.