posted on 2014-09-25, 00:00authored byGeorge Kokotos, Astrid J. Feuerherm, Efrosini Barbayianni, Ishita Shah, Mari Sæther, Victoria Magrioti, Thuy Nguyen, Violetta Constantinou-Kokotou, Edward A. Dennis, Berit Johansen
Group IVA cytosolic
phospholipase A2 (GIVA cPLA2) is the rate-limiting
provider of pro-inflammatory mediators in many tissues and is thus
an attractive target for the development of novel anti-inflammatory
agents. In this work, we present the synthesis of new thiazolyl ketones
and the study of their activities in vitro, in cells, and in vivo.
Within this series of compounds, methyl 2-(2-(4-octylphenoxy)acetyl)thiazole-4-carboxylate
(GK470) was found to be the most potent inhibitor of GIVA cPLA2, exhibiting an XI(50) value of
0.011 mole fraction in a mixed micelle assay and an IC50 of 300 nM in a vesicle assay. In a cellular assay using SW982 fibroblast-like
synoviocytes, it suppressed the release of arachidonic acid with an
IC50 value of 0.6 μM. In a prophylactic collagen-induced
arthritis model, it exhibited an anti-inflammatory effect comparable
to the reference drug methotrexate, whereas in a therapeutic model,
it showed results comparable to those of the reference drug Enbrel.
In both models, it significantly reduced plasma PGE2 levels.