title: Design, synthesis, and biological evaluation of 1,5-diaryl-1,2,4-triazole derivatives as selective cyclooxygenase-2 inhibitors.
abstract: A series of 1,5-diaryl-1,2,4-triazole derivatives were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b, 6b, 6c, 7c, 8b, 8d, 9c, and 9d have potent anti-inflammatory activity (P < 0.01), while compounds 6b, 6c, and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX-2 (COX-2 IC(50) = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX-2 IC(50) = 0.26 µM; SI = 0.015). In a rat carrageenan-induced paw edema assay, 6c exhibited moderate anti-inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX-2 in a similar mode to that of the known selective COX-2 inhibitor SC-558.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Meng-Jie
authors.initials: MJ
authors.lastname: Li
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Xu
authors.forename: Yong-Na
authors.initials: YN
authors.lastname: Zhang
authors.forename: Qiu-Juan
authors.initials: QJ
authors.lastname: Wang
authors.forename: Ni-Yue
authors.initials: NY
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002351:Carrageenan; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D011485:Protein Binding; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D014230:Triazoles; D002351:Carrageenan; D000068579:Celecoxib