Highly Potent 2-Oxoester Inhibitors of Cytosolic Phospholipase A

Cytosolic phospholipase A2 (GIVA cPLA2) has attracted great interest as a medicinal target because it initiates the eicosanoid cascade and is involved in a number of inflammatory diseases. As a consequence, the development of potent synthetic inhibitors is of great importance. We have developed highly potent 2-oxoester inhibitors of GIVA cPLA2 presenting XI(50) values between 0.000019 and 0.000066. We demonstrate that the 2-oxoester functionality is essential for in vitro inhibitory activity, making these inhibitors useful research reagents. However, their high reactivity results in rapid degradation of the inhibitors in human plasma, limiting their pharmaceutical utility without further modification.