Selective cyclooxygenase-2 inhibitors: Heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents

I. K. Khanna, Y. Yu, R. M. Huff, R. M. Weier, X. Xu, F. J. Koszyk, P. W. Collins, J. N. Cogburn, P. C. Isakson, C. M. Koboldt, J. L. Masferrer, W. E. Perkins, K. Seibert, A. W. Veenhuizen, J. Yuan, D. C. Yang, Y. Y. Zhang

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109 Scopus citations

Abstract

A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2.3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED50 = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED50 = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.

Original languageEnglish
Pages (from-to)3168-3185
Number of pages18
JournalJournal of Medicinal Chemistry
Volume43
Issue number16
DOIs
StatePublished - Aug 10 2000

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    Khanna, I. K., Yu, Y., Huff, R. M., Weier, R. M., Xu, X., Koszyk, F. J., Collins, P. W., Cogburn, J. N., Isakson, P. C., Koboldt, C. M., Masferrer, J. L., Perkins, W. E., Seibert, K., Veenhuizen, A. W., Yuan, J., Yang, D. C., & Zhang, Y. Y. (2000). Selective cyclooxygenase-2 inhibitors: Heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents. Journal of Medicinal Chemistry, 43(16), 3168-3185. https://doi.org/10.1021/jm0000719