1,2-Diarylimidazoles as Potent, Cyclooxygenase-2 Selective, and Orally Active Antiinflammatory Agents

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 (<BO>I</BO>) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC<INF>50</INF> = 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 CF<INF>3</INF> 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., ED<INF>50</INF> = 0.02 mpk for <BO>22</BO> and <BO>34</BO>). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED<INF>50</INF> = 9−30 mpk) and hyperalgesia (ED<INF>50</INF> = 11−40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.