Selective cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents
| Autor: | Rita M. Huff, Yan Zhang, A. W. Veenhuizen, Jing Yuan, Karen Seibert, D.-C. Yang, Xiangdong Xu, C. M. Koboldt, P. W. Collins, Yi Yu, Richard Weier, J. N. Cogburn, Koszyk Francis, J. Masferrer, W. E. Perkins, Ish Kumar Khanna, Peter C. Isakson |
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| Rok vydání: | 2000 |
| Předmět: |
Stereochemistry
Pyridines Administration Oral Chemical synthesis Prostaglandin-endoperoxide synthase 2 chemistry.chemical_compound Mice Structure-Activity Relationship Dogs Pharmacokinetics Oral administration Drug Discovery Nitriles Animals Edema Humans Cyclooxygenase Inhibitors Thiazole Sulfonamides biology Cyclooxygenase 2 Inhibitors Anti-Inflammatory Agents Non-Steroidal Stomach Imidazoles Membrane Proteins Arthritis Experimental Carrageenan Rats Intestines Isoenzymes chemistry Enzyme inhibitor Cyclooxygenase 2 Hyperalgesia Prostaglandin-Endoperoxide Synthases biology.protein Molecular Medicine Cyclooxygenase Gastrointestinal Hemorrhage |
| Zdroj: | Journal of medicinal chemistry. 43(16) |
| ISSN: | 0022-2623 1000-9000 |
| Popis: | 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, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 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. |
| Databáze: | OpenAIRE |
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