Synthesis and Structure−Activity Relationship of a New Series of COX-2 Selective Inhibitors:  1,5-Diarylimidazoles

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 pa...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-07, Vol.46 (16), p.3463-3475
Main Authors: Almansa, Carmen, Alfón, José, de Arriba, Alberto F, Cavalcanti, Fernando L, Escamilla, Ignasi, Gómez, Luis A, Miralles, Agustí, Soliva, Robert, Bartrolí, Javier, Carceller, Elena, Merlos, Manuel, García-Rafanell, Julián
Format: Article
Language:English
Subjects:
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Arthritis, Experimental - drug therapy
Binding Sites
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cell Line
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors - chemical synthesis
Cyclooxygenase Inhibitors - chemistry
Cyclooxygenase Inhibitors - pharmacology
Dinoprostone - biosynthesis
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Inflammation - metabolism
Isoenzymes - antagonists & inhibitors
Male
Medical sciences
Membrane Proteins
Models, Molecular
Pain Measurement
Peptic Ulcer - chemically induced
Pharmacology. Drug treatments
Prostaglandin-Endoperoxide Synthases
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030765s