Authors
George Kokotos, Astrid J Feuerherm, Efrosini Barbayianni, Ishita Shah, Mari Sæther, Victoria Magrioti, Thuy Nguyen, Violetta Constantinou-Kokotou, Edward A Dennis, Berit Johansen
Publication date
2014/9/25
Journal
Journal of medicinal chemistry
Volume
57
Issue
18
Pages
7523-7535
Publisher
American Chemical Society
Description
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 …
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