| Autor: |
Khanna, I. K., Weier, R. M., Yu, Y., Xu, X. D., Koszyk, F. J., Collins, P. W., Koboldt, C. M., Veenhuizen, A. W., Perkins, W. E., Casler, J. J., Masferrer, J. L., Zhang, Y. Y., Gregory, S. A., Seibert, K., Isakson, P. C. |
| Zdroj: |
Journal of Medicinal Chemistry; May 23, 1997, Vol. 40 Issue: 11 p1634-1647, 14p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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