title: A novel indazolo-triazolo-benzotriazepine exerts anti-inflammatory effects by inhibition of cyclooxygenase-2 activity and nitric oxide synthase-2 expression.
abstract: We have studied the anti-inflammatory activity of (6-(p-bromophenyl)amino-7-(p-chlorophenyl)indazolo[2',3':1,5]-1,2,4-triazolo[4,3-a]-1,3,5-benzotriazepine (ITB), prepared by solid-phase synthesis. This novel compound reduced the production of nitrite and PGE(2) in RAW 264.7 macrophages stimulated with lipopolysaccharide in a concentration-dependent manner. The first effect was dependent on inhibition of nitric oxide synthase-2 (NOS-2) protein expression although ITB did not modify nuclear factor-kappa B (NF-kappa B)-DNA binding. In addition, this compound inhibited cyclooxygenase-2 (COX-2) activity, which was also observed in aspirin-treated human monocytes. The anti-inflammatory effects of ITB were demonstrated in the carrageenan-induced mouse paw oedema, where this compound inhibited swelling and PGE(2) levels in inflamed paws but not in stomachs, in contrast to the dual COX-1/COX-2 inhibitor indomethacin. Inhibition of COX-2 activity and NOS-2 protein expression was confirmed in vivo using the zymosan-injected mouse air pouch model. These results suggest that synthesis of fused indazolo bis(guanidines) is a useful approach in the search for new anti-inflammatory agents.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Av. Vicent Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Guillén
authors.forename: Amalia
authors.initials: A
authors.lastname: Ubeda
authors.forename: Pablo
authors.initials: P
authors.lastname: López-Cremades
authors.forename: Enrique
authors.initials: E
authors.lastname: Aller
authors.forename: Angeles
authors.initials: A
authors.lastname: Lorenzo
authors.forename: Pedro
authors.initials: P
authors.lastname: Molina
authors.forename: M José
authors.initials: MJ
authors.lastname: Alcaraz
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D015153:Blotting, Western; D002351:Carrageenan; D002470:Cell Survival; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000188:drug therapy; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C484507:6-(p-bromophenyl)amino-7-(p-chlorophenyl)indazolo(2',3':1,5)-1,2,4-triazolo(4,3-a)-1,3,5-benzotriazepine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007191:Indazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D009573:Nitrites; D014230:Triazoles; D002351:Carrageenan; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone