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., TNFα, ICAM-1, VCAM-1) is NF-κB-dependent. IκB kinase is critical in transducing the signal-inducible activation of NF-κB 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 IκB kinase, inhibited the TNFα-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 (IC₅₀ ≅ 5 μM). 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 IκB 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.