Abstract
The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Arthritis, Experimental / drug therapy
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Binding Sites
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Cell Line
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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 / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / biosynthesis
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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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Inflammation / metabolism
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Isoenzymes / antagonists & inhibitors*
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Male
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Membrane Proteins
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Models, Molecular
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Pain Measurement
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Peptic Ulcer / chemically induced
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Prostaglandin-Endoperoxide Synthases
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Rats
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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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4-(4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl)benzenesulfonamide
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Analgesics
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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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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone