Potent and selective 2-oxoamide inhibitors of phospholipases A2 as novel medicinal agents for the treatment of inflammatory diseases

摘要

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 GILA sPLA2 is involved in cardiovascular diseases. We have developed lipophilic 2-oxoamides based on (S)-γ-or 8-amino acids as potent and selective inhibitors of GIVA cPLA2, which present interesting in vivo anti-inflammatory activity. 2-Oxoamides based on natural a-amino acids are selective inhibitors of GUA sPLA2. The mode of binding of 2-oxoamides with either GIVA cPLA2 or GIIA sPLA2 has been studied by various techniques.