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

  • J Med Chem. 2010 May 13;53(9):3602-10. doi: 10.1021/jm901872v.
George Kokotos  1 ,  Yuan-Hao Hsu ,  John E Burke ,  Constantinos Baskakis ,  Christoforos G Kokotos ,  Victoria Magrioti ,  Edward A Dennis
Affiliations
  • 1. Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece. [email protected]
PMID: 20369880 DOI: 10.1021/jm901872v
Abstract

Group VIA calcium-independent Phospholipase A(2) (GVIA iPLA(2)) has recently emerged as a novel pharmaceutical target. We have now explored the structure-activity relationship between fluoroketones and GVIA iPLA(2) 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 iPLA(2) (X(I)(50) = 0.0002) ever reported. Being 195 and >455 times more potent for GVIA iPLA(2) than for GIVA cPLA(2) and GV sPLA(2), 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 iPLA(2) with a X(I)(50) value of 0.001 while inhibiting the Other intracellular GIVA cPLA(2) and GV sPLA(2) 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.

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