title: Synthesis and biological evaluation of isoxazolo[4,5-d]pyridazin-4-(5H)-one analogues as potent anti-inflammatory agents.
abstract: In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28-30 showed dual COX-2 (IC(50)'s in the 2.1-10.9 μM range), and 5-LOX (IC(50)'s in the 6.3-63.5 μM range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30-45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC(50)=2.1 μM) and 5-LOX (IC(50)=6.3 μM) enzymes. We investigated the binding interactions of compound 28 by an enzyme-ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index=0.25) compared to the reference drug ibuprofen (UI=7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Hacettepe, 06100 Sihhiye, Ankara, Turkey.
authors.forename: Keriman
authors.initials: K
authors.lastname: Özadalı
authors.forename: Fügen
authors.initials: F
authors.lastname: Özkanlı
authors.forename: Sarthak
authors.initials: S
authors.lastname: Jain
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D016859:Lipoxygenase Inhibitors; D011724:Pyridazines; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2