1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents

Ish K. Khanna, Richard M. Weier, Yi Yu, Xiang D. Xu, Francis J. Koszyk, Paul W. Collins, Carol M. Koboldt, Amy W. Veenhuizen, William E. Perkins, Jacquelen J. Casier, Jaime L. Masferrer, Yan Y. Zhang, Susan A. Gregory, Karen Seibert, Peter C. Isakson

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211 Scopus citations


Series of 1,2-diarylimidazoles has been synthesized and found to contain highly potent and selective inhibitors of the human COX-2 enzyme. The paper describes a short synthesis of the target 1,2-diarylimidazoles starting with aryl nitriles. Different portions of the diarylimidazole (I) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC50 = 10-100 nm) and selective (1000-12500) inhibitors of the COX-2 enzyme. The study on the influence of substituents in the imidazole ring established that a CF3 group at position 4 gives the optimum oral activity. A number of the diarylimidazoles showed excellent inhibition in the adjuvant induced arthritis model (e.g., ED50 = 0.02 mpk for 22 and 34). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED50 = 9-30 mpk) and hyperalgesia (ED50 = 11- 40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.

Original languageEnglish
Pages (from-to)1634-1647
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number11
StatePublished - May 23 1997


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