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New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2

Citation:

Magrioti V, Nikolaou A, Smyrniotou A, Shah I, Constantinou-Kokotou V, Dennis EA, Kokotos G. New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2. Bioorganic and Medicinal Chemistry. 2013;21:5823-5829.

Abstract:

Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2.