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