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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kokotos G,Hsu YH,Burke JE,Baskakis C,Kokotos CG,Magrioti V,Dennis EA

doi

10.1021/jm901872v

subject

Has Abstract

pub_date

2010-05-13 00:00:00

pages

3602-10

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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