The 2′-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor | Zendy

Anna L. Blobaum | Zendy; Md. Jashim Uddin | Zendy; Andrew S. Felts | Zendy; Brenda C. Crews | Zendy; Carol A. Rouzer | Zendy; Lawrence J. Marnett | Zendy

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

Author(s) -

Anna L. Blobaum,

Md. Jashim Uddin,

Andrew S. Felts,

Brenda C. Crews,

Carol A. Rouzer,

Lawrence J. Marnett

Publication year - 2013

Publication title -

acs medicinal chemistry letters

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.065

H-Index - 66

ISSN - 1948-5875

DOI - 10.1021/ml400066a

Subject(s) - in vivo , cyclooxygenase , trifluoromethyl , potency , chemistry , ic50 , pharmacology , enzyme , cox 2 inhibitor , selectivity , sulfone , enzyme inhibitor , edema , indometacin , stereochemistry , medicine , biochemistry , in vitro , biology , alkyl , microbiology and biotechnology , organic chemistry , polymer chemistry , catalysis , prostaglandin endoperoxide synthase

Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2'-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'-methyl group of indomethacin with trifluoromethyl produces CF 3 -indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC 50 mCOX-2 = 267 nM; IC 50 oCOX-1 > 100 μM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF 3 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. CF 3 -indomethacin 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.

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