The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.
- Klíčová slova
- glycosaminoglycan, heparin binding protein, inflammation, neutrophil, sepsis,
- MeSH
- antiflogistika farmakologie MeSH
- buněčná adheze účinky léků MeSH
- cékum mikrobiologie chirurgie MeSH
- chinazolinony farmakologie MeSH
- edém chemicky indukované metabolismus patologie prevence a kontrola MeSH
- glykosaminoglykany metabolismus MeSH
- infiltrace neutrofily účinky léků MeSH
- ligace MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- neutrofily účinky léků metabolismus mikrobiologie MeSH
- pankreatitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- peritonitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- punkce MeSH
- sepse metabolismus mikrobiologie patologie prevence a kontrola MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika MeSH
- chinazolinony MeSH
- glykosaminoglykany MeSH
OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.
- Klíčová slova
- Autoimmune disease, Glycosaminoglycan, Heparan sulfate, Heparin binding protein, Inflammation, Small molecule drug,
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- encefalitogenní základní proteiny imunologie MeSH
- encefalomyelitida autoimunitní experimentální farmakoterapie imunologie MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků imunologie MeSH
- heparitinsulfát metabolismus MeSH
- kolitida chemicky indukované farmakoterapie imunologie MeSH
- krysa rodu Rattus MeSH
- kyselina trinitrobenzensulfonová MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- nádorové buněčné linie MeSH
- oxazolon MeSH
- potkani inbrední LEW MeSH
- pozdní přecitlivělost chemicky indukované farmakoterapie imunologie MeSH
- pyridiny farmakologie terapeutické užití MeSH
- rolling leukocytů účinky léků MeSH
- T-lymfocyty účinky léků imunologie MeSH
- thiofeny farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika MeSH
- encefalitogenní základní proteiny MeSH
- heparitinsulfát MeSH
- kyselina trinitrobenzensulfonová MeSH
- oxazolon MeSH
- pyridiny MeSH
- RX-111 MeSH Prohlížeč
- thiofeny MeSH
