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

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.

Silica supported heteropolyacid catalyzed dehydration of aldoximes to nitriles and alcohols to alkenes

“…They also act as key intermediates for several pharmaceuticals, agrochemicals, dyes, and electro-optical materials (1Á6). Nitriles are also used as precursors of tetrazole analogs, which are used as antipicornavirus drugs (7), triazo [1,5-c] pyrimidines with potential antiasthama activity (8), and commercially important angiotensin 1 receptor ligands, losartan, and valsartan (9). The traditional method for the synthesis of aromatic nitriles from aryl bromides/iodides requires a stoichiometric amount of Cu (I) cyanide at elevated temperatures (10,11).…”

Synthesis of 2,4,5-Trisubstituted Phenanthroimidazole Derivatives using SBA-Pr-SO3H as a Nanocatalyst

“…8,9 Additionally, derivatives of imidazole conjugated with aromatic rings have been widely used as fluorescent dyes. 10 In recent years, several methods have been reported for the preparation of three-substituted imidazole derivatives from 9,10-phenanthraquinones, benzaldehyde derivatives and ammonium acetate using different catalysts such as I 2 , 11 mercaptopropylsilica, 12 zirconium Schiff base, 13 iron(III) triflate, 14 sulfamic acid, 15 and ionic liquid modified surface.…”

An Efficient, Solvent Free One Pot Synthesis of Tetra substitue dimidazoles Catalyzed by Nanocrystalline γ-alumina

“…Imidazole and its analogues are centre of attraction for researchers around the globe due to their diverse bioactivities. Imidazole derivatives were reported to be involved in the biosynthesis of interleukin-1 (IL-1) 2 and were also reported to function as cyclooxygenase-2 (COX-2) [3] B-Raf kinase 4 , transforming growth factor b1 (TGF-b1) type 1 activin receptor-like kinase (ALk5) 5 and p38 MAP kinase 6 inhibitors. Appropriately substituted imidazoles were used as CB1 cannabinoid receptor antagonists 7 , modulators of P-glycoprotein (P-gp) mediated multidrug resistance (MDR) 8 and glucagon receptors 9 .…”