1,2-DIARYLIMIDAZOLES AS POTENT, CYCLOOXYGENASE-2 SELECTIVE, AND ORALLY-ACTIVE ANTIINFLAMMATORY AGENTS

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