The 2鈥?Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor

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• 作者：Anna L. Blobaum ; Md. Jashim Uddin ; Andrew S. Felts ; Brenda C. Crews ; Carol A. Rouzer ; Lawrence J. Marnett
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：4
• 期：5
• 页码：486-490
• 全文大小：290K
• 年卷期：v.4,no.5(May 9, 2013)
• ISSN：1948-5875

文摘

Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2鈥?methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2鈥?methyl group of indomethacin with trifluoromethyl produces CF₃鈥搃ndomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC₅₀ mCOX-2 = 267 nM; IC₅₀ oCOX-1 > 100 渭M). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF₃ group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF₃鈥搃ndomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin.

Keywords:

Cyclooxygenase; inflammation; nonsteroidal anti-inflammatory drug; coxib; prostaglandin; arachidonic acid