Selective Cyclooxygenase-2 Inhibitors: Heteroaryl Modified 1,2-Diarylimidazoles Are Potent, Orally Active Antiinflammatory Agents

• DOI: 10.1021/jm0000719
• Publication Date: 2002-07-26T05:59:58Z
• Authors: Ish K. Khanna; Yi Yu; Renee M. Huff; Richard M. Weier; Xiangdong Xu; Francis J. Koszyk; Paul W. Collins; J. Nita Cogburn; Peter C. Isakson; Carol M. Koboldt; Jaime L. Masferrer; William E. Perkins; Karen Seibert; Amy W. Veenhuizen; Jinhua Yuan; Dai-Chang Yang; Yan Y. Zhang
• Keywords: ED50; Carrageenan; Thiazole; Orally active; Active metabolite

A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent highly selective (1000-9000-fold) inhibitors the human COX-2. 3-Pyridyl derived COX-2 inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) chronic (adjuvant arthritis, 0.25 models inflammation. The relatively long half-life 25 rat dog prompted investigation pyridyl other heteroaromatic systems containing potential metabolic functionalities. number substituted thiazole compounds (e.g., 44, 46, 54, 76, 78) demonstrated oral every efficacy model evaluated. Several orally active diarylimidazoles desirable pharmacokinetics profiles showed no GI toxicity up 100 mg/kg both models. paper describes facile practical syntheses targeted diarylimidazoles. structure-activity relationships antiinflammatory properties a are discussed.