UC San Diego

Calcium-independent phospholipase A₂ (GVIA iPLA₂) has recently attracted interest as a medicinal target. The number of known GVIA iPLA₂ inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA₂ and their selectivity over the other major intracellular GIVA cPLA₂ and the secreted GV sPLA₂. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA₂ (X_I(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA₂ and GV sPLA₂.