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

• Published in: Journal of medicinal chemistry Vol. 40; no. 11; pp. 1634 - 1647
• Main Authors: Khanna, Ish K, Weier, Richard M, Yu, Yi, Xu, Xiang D, Koszyk, Francis J, Collins, Paul W, Koboldt, Carol M, Veenhuizen, Amy W, Perkins, William E, Casler, Jacquelen J, Masferrer, Jaime L, Zhang, Yan Y, Gregory, Susan A, Seibert, Karen, Isakson, Peter C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.05.1997; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Arthritis, Experimental - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan; Chemistry, Medicinal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Edema - chemically induced; Edema - drug therapy; Gastrointestinal Diseases - chemically induced; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; Isoenzymes; Life Sciences & Biomedicine; Medical sciences; Membrane Proteins; Mice; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases; Rats; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Sulfones - chemical synthesis; Sulfones - pharmacology; Sulfones - therapeutic use; SYNTHASE; RHEUMATIC DISEASES; INDUCIBLE CYCLOOXYGENASE; THERAPEUTIC EFFICACY; MESSENGER-RNA; ANTI-INFLAMMATORY DRUG; COX-2 INHIBITORS; ASPIRIN; PROSTAGLANDIN SYNTHESIS; 1,2-DIARYLCYCLOPENTENES; Imidazole derivatives; Prostaglandin-endoperoxide synthase; Sulfonamide; Rat; Sulfone; Enzyme; Nitrogen heterocycle; Toxicity; Rodentia; Antiinflammatory agent; Oral administration; Enzyme inhibitor; Gastrointestinal; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Chlorine Organic compounds; Oxidoreductases; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9700225

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.