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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Arthritis, Experimental / drug therapy
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Carrageenan
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Cyclooxygenase 1
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / therapeutic use
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Edema / chemically induced
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Edema / drug therapy
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Gastrointestinal Diseases / chemically induced
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Imidazoles / therapeutic use
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Isoenzymes*
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Membrane Proteins
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Mice
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Molecular Structure
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Prostaglandin-Endoperoxide Synthases*
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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Sulfones / chemical synthesis*
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Sulfones / pharmacology
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Sulfones / therapeutic use
Substances
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2-(3-chlorophenyl)-4-trifluoromethyl-1-(4-methylsulfonylphenyl)imidazole
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4-(2-(3-chlorophenyl)-4-trifluoromethylimidazol-1-yl)benzenesulfonamide
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Imidazoles
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Isoenzymes
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Membrane Proteins
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Sulfonamides
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Sulfones
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Carrageenan
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Cyclooxygenase 1
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Cyclooxygenase 2
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PTGS1 protein, human
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Ptgs1 protein, mouse
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Ptgs1 protein, rat