title: 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).
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.
authors.affiliation: Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. hiromasa.hashimoto@imj.jti.co.jp
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Imamura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Haruta
authors.forename: Korekiyo
authors.initials: K
authors.lastname: Wakitani
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001557:Benzenesulfonates / Q000737:chemistry* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins; D008956:Models, Chemical; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D013696:Temperature; D000096926:Benzenesulfonamides
chemical_list: D000893:Anti-Inflammatory Agents; D001557:Benzenesulfonates; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005461:Fluorine; D007527:Isoenzymes; D008565:Membrane Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human