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Pure Appl. Chem., 2012, Vol. 84, No. 9, pp. 1877-1894

Published online 2012-05-25

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

Efrosini Barbayianni1, Georgia Antonopoulou2 and George Kokotos2,1*

1 Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
2 Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou Avenue 48, 11635 Athens, Greece

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.