Inhibition of Group IVA Cytosolic Phospholipase A<INF>2</INF> by Novel 2-Oxoamides in Vitro, in Cells, and in Vivo

The Group IVA cytosolic phospholipase A<INF>2</INF> (GIVA PLA<INF>2</INF>) is a particularly attractive target for drug development because it is the rate-limiting provider of proinflammatory mediators. We previously reported the discovery of novel 2-oxoamides that inhibit GIVA PLA<INF>2</INF> [Kokotos, G.; et al. J. Med. Chem. <BO>2002</BO>, 45, 2891−2893]. In the present work, we have further explored this class of inhibitors and found that the 2-oxoamide functionality is more potent when it contains a long 2-oxoacyl residue and a free carboxy group. Long-chain 2-oxoamides based on γ-aminobutyric acid and γ-norleucine are potent inhibitors of GIVA PLA<INF>2</INF>. Such inhibitors act through a fast and reversible mode of inhibition in vitro, are able to block the production of arachidonic acid and prostaglandin E<INF>2</INF> in cells, and demonstrate potent in vivo anti-inflammatory and analgesic activity.