Abstract | OBJECTIVE: RESULTS: Here we show that BMS-345541, a highly selective inhibitor of IkappaB kinase, inhibited the TNFalpha-induced expression of both ICAM-1 and VCAM-1 in human umbilical vein endothelial cells at the same concentration range as cytokine expression is inhibited in monocytic cells (IC(50) congruent with 5 microM). Against dextran sulfate sodium-induced colitis in mice, BMS-345541 administered orally at doses of 30 and 100 mg/kg was effective in blocking both clinical and histological endpoints of inflammation and injury. CONCLUSION: This represents the first example of an inhibitor of IkappaB kinase with anti-inflammatory activity in vivo and indicates that inhibitors of IkB kinase show the promise of being highly efficacious in inflammatory disorders such as inflammatory bowel disease.
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Authors | J F MacMaster, D M Dambach, D B Lee, K K Berry, Y Qiu, F C Zusi, J R Burke |
Journal | Inflammation research : official journal of the European Histamine Research Society ... [et al.]
(Inflamm Res)
Vol. 52
Issue 12
Pg. 508-11
(Dec 2003)
ISSN: 1023-3830 [Print] Switzerland |
PMID | 14991079
(Publication Type: Journal Article)
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Chemical References |
- 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
- Cell Adhesion Molecules
- Imidazoles
- Quinoxalines
- Tumor Necrosis Factor-alpha
- Vascular Cell Adhesion Molecule-1
- Intercellular Adhesion Molecule-1
- Sulfasalazine
- Dextran Sulfate
- Protein Serine-Threonine Kinases
- CHUK protein, human
- Chuk protein, mouse
- I-kappa B Kinase
- IKBKB protein, human
- IKBKE protein, human
- Ikbkb protein, mouse
- Ikbke protein, mouse
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Topics |
- Animals
- Cell Adhesion Molecules
(metabolism)
- Cells, Cultured
- Colitis
(chemically induced, drug therapy, metabolism, pathology)
- Dextran Sulfate
(pharmacology)
- Disease Models, Animal
- Endothelial Cells
(drug effects, metabolism)
- Gene Expression Regulation
(drug effects)
- Humans
- I-kappa B Kinase
- Imidazoles
(chemistry, pharmacology, therapeutic use)
- Intercellular Adhesion Molecule-1
(metabolism)
- Mice
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, metabolism)
- Quinoxalines
(chemistry, pharmacology, therapeutic use)
- Sulfasalazine
(pharmacology)
- Tumor Necrosis Factor-alpha
(pharmacology)
- Vascular Cell Adhesion Molecule-1
(metabolism)
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