Inhibition of Group IVA Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo, and in Vivo

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• 作者：George Kokotos ; Astrid J. Feuerherm ; Efrosini Barbayianni ; Ishita Shah ; Mari S忙ther ; Victoria Magrioti ; Thuy Nguyen ; Violetta Constantinou-Kokotou ; Edward A. Dennis ; Berit Johansen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7523-7535
• 全文大小：571K
• ISSN：1520-4804

文摘

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 X_I(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 渭M. 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.