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

Citations Over TimeTop 10% of 1997 papers

Abstract

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.

Related Papers

• → Structure−Activity Relationships at the 5-Position of Thiolactomycin: An Intact (5R)-Isoprene Unit Is Required for Activity against the Condensing Enzymes from Mycobacterium tuberculosis and Escherichia coli(2005)80 cited
• → Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor(2011)23 cited
• → High-Resolution Structures of Human Aldose Reductase Holoenzyme in Complex with Stereoisomers of the Potent Inhibitor Fidarestat: Stereospecific Interaction between the Enzyme and a Cyclic Imide Type Inhibitor(2004)28 cited
• → Design and synthesis of lignostilbene-α,β-dioxygenase inhibitors(2002)16 cited
• → Diarylsemicarbazones: synthesis, antineoplastic activity and topoisomerase I inhibition assay(1999)19 cited