2-OXAMIDE INHIBITORS OF PHOSPHOLIPASE A2 ACTIVITY AND CELLULAR ARACHIDONATE RELEASE BASED ON DIPEPTIDES AND PSEUDOPEPTIDES

摘要

The disclosure provides a series of 2-oxoamides based on dipeptides and pseudodipeptides, which were synthesized and their activities toward two human intracellular phospholipases A2 (GIVA CPLA₂ and GVIA 1PLA₂) and one human secretory phospholipase A2 (GV sPLA₂) were evaluated. Derivatives containing a free carboxyl group are selective GIVA cPLA₂ inhibitors. A derivative based on the ethyl ester of an ether pseudodipeptide is the first 2-oxoamide, which preferentially inhibits GVIA iPLA₂. The effect of 2-oxoamides on the generation of arachidonic acid from RAW 264.7 macrophages was also studied. It was found that selective GIVA cPLA₂ inhibitors preferentially inhibited cellular arachidonic acid release; in which one pseudodipeptide gave an IC50 value of 2 μM.