title: Anti-inflammatory activity of a pteridine derivative (4AZA2096) alleviates TNBS-induced colitis in mice.
abstract: Elevated production of tumor necrosis factor (TNF) plays a central role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis and Crohn's disease. Naturally occurring pteridine analogs have been reported to have potent immunomodulatory activity, especially on TNF production. The aim of this study is to identify small molecule TNF inhibitiors derived from pteridine and to prove their in vivo efficacy in an inflammatory model. A focused chemical library based on the pteridine scaffold was screened in vitro on lipopolysaccharide (LPS)-induced TNF production in peripheral blood mononuclear cells (PBMC). One synthetic pteridine analog (4AZA2096), shown to have strong inhibitory activity, was selected and tested for its efficacy to treat trinitrobenzenesulfonate (TNBS)-induced colitis in mice, a model of Crohn's disease. Colitis was induced by rectal administration of 1 mg TNBS in 50% ethanol after presensitization via the skin. The synthetic pteridine analog 4AZA2096 was shown to potently inhibit LPS-induced TNF production in vitro. Colitic mice treated with 4AZA2096 orally (20 mg/kg/day) recovered more rapidly and, histologically, had a reduction of inflammatory lesions, less edema, a reduction of goblet cell loss, and reduced wall thickness. Cell infiltration in the colon, especially infiltration of neutrophils, as shown by myeloperoxidase (MPO) activity, was reduced in 4AZA2096-treated animals. Intralesional TNF production was lower in mice of the treated groups, whereas interleukin-18 (IL-18) and interferon-gamma (IFN-gamma) mRNA were not affected. Treatment had no effect on anti-TNBS antibody production, arguing against generalized immunosuppression. In conclusion, we identified a pteridine derivative, 4AZA2096, with strong inhibitory activity on TNF production and a remission- inducing effect in TNBS colitis, supporting further preclinical and clinical development of this novel TNF inhibitor for treatment of inflammatory diseases.
authors.affiliation: Laboratory of Experimental Immunology, Faculty of Medicine, Katholieke Universiteit Leuven, Belgium.
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.forename: Ellen
authors.initials: E
authors.lastname: Dillissen
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kasran
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Gavin
authors.initials: G
authors.lastname: Clydesdale
authors.forename: Ilse
authors.initials: I
authors.lastname: Sienaert
authors.forename: Steven De
authors.initials: SD
authors.lastname: Jonghe
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Gao
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000906:Antibodies / Q000097:blood; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000201:enzymology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: C513594:4AZA2096; D000893:Anti-Inflammatory Agents; D000906:Antibodies; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011621:Pteridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase