An inhibitor of IkappaB kinase, BMS-345541, blocks endothelial cell adhesion molecule expression and reduces the severity of dextran sulfate sodium-induced colitis in mice

Inflamm Res. 2003 Dec;52(12):508-11. doi: 10.1007/s00011-003-1206-4. Epub 2003 Nov 13.

Abstract

Objective: Inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are characterized by chronic relapsing inflammation. The transcription of many of the proteins which mediate the pathogenesis in inflammatory bowel disease (e.g., TNFalpha, ICAM-1, VCAM-1) is NF-kappaB-dependent. IkappaB kinase is critical in transducing the signal-inducible activation of NF-kappaB and, therefore, represents a potentially promising target for the development of novel agents to treat inflammatory bowel disease and other inflammatory diseases.

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.

MeSH terms

  • Animals
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Colitis / metabolism
  • Colitis / pathology*
  • Dextran Sulfate / pharmacology*
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Gene Expression Regulation / drug effects*
  • Humans
  • I-kappa B Kinase
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Quinoxalines / therapeutic use
  • Sulfasalazine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • 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