Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2

Article abstract of DOI:10.1021/jm901872v

Group VIA calcium-independent phospholipase A₂ (GVIA iPLA ₂) has recently emerged as a novel pharmaceutical target. We have now explored the Structure-activity relationship between fluoroketones and GVIA iPLA₂ inhibition. The presence of a naphthyl group proved to be of paramount importance. 1,1,1-Trifluoro-6-(naphthalen-2-yl)hexan-2-one (FKGK18) is the most potent inhibitor of GVIA iPLA₂ (X_I(50) = 0.0002) ever reported. Being 195 and >455 times more potent for GVIA iPLA ₂ than for GIVA cPLA₂ and GV sPLA₂, respectively, makes it a valuable tool to explore the role of GVIA iPLA ₂ in cells and in vivo models. 1,1,1,2,2,3,3-Heptafluoro-8- (naphthalene-2-yl)octan-4-one inhibited GVIA iPLA₂ with a X _I(50) value of 0.001 while inhibiting the other intracellular GIVA cPLA₂ and GV sPLA₂ at least 90 times less potently. Hexa- and octafluoro ketones were also found to be potent inhibitors of GVIA iPLA ₂; however, they are not selective.