Abstract
A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.
MeSH terms
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Arthritis, Rheumatoid / drug therapy
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Benzenesulfonates / chemistry*
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Benzenesulfonates / pharmacology*
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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 / pharmacology*
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Fluorine / chemistry
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Humans
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Inhibitory Concentration 50
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / chemistry*
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Isoenzymes / metabolism
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Membrane Proteins
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Models, Chemical
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Oxazoles / chemical synthesis*
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Oxazoles / chemistry*
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Oxazoles / pharmacology*
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Prostaglandin-Endoperoxide Synthases / chemistry*
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Prostaglandin-Endoperoxide Synthases / metabolism
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
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Temperature
Substances
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4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide
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Anti-Inflammatory Agents
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Benzenesulfonates
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Oxazoles
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Sulfonamides
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Fluorine
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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