Novel inhibitors of cytokine-induced I kappa B alpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo

We have identified two compounds that inhibit the expression of endothelial-leukocyte adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, These compounds act by inhibiting tumor necrosis factor-alpha-induced phosphorylation of I kappa B-alpha, resulting in decreased nuclear factor-kappa B and decreased expression of adhesion molecules, The effects on both I kappa B-alpha phosphorylation and surface expression of E-selectin were irreversible and occurred at an IC50 of approximately 10 mu M. These agents selectively and irreversibly inhibited the tumor necrosis factor-alpha-inducible phosphorylation of I kappa B-alpha without affecting the constitutive I kappa B-alpha Phosphorylation. Although these compounds exhibited other activities, including stimulation of the stress-activated protein kinases, p38 and JNK-1, and activation of tyrosine phosphorylation of a 130-140-kDa protein, these effects are probably distinct from the effects on adhesion molecule expression since they were reversible, One compound was evaluated in vivo and shown to be a potent anti-inflammatory drug in two animal models of inflammation, The compound reduced edema formation in a dose-dependent manner in the rat carrageenan paw edema assay and reduced pam swelling in a rat adjuvant arthritis model, These studies suggest that inhibitors of cytokine-inducible I kappa B alpha phosphorylation exert anti-inflammatory activity in vivo.