This study identifies two novel compounds, compound 1 and compound 2, that inhibit the expression of endothelial-leukocyte adhesion molecules (E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) by selectively inhibiting tumor necrosis factor-α (TNFα)-induced phosphorylation of IκB-α. These compounds irreversibly stabilize IκB-α, leading to decreased nuclear translocation of NF-κB and reduced expression of adhesion molecules. Compound 1 also increases the activity of stress-activated protein kinases p38 and JNK-1, but does not affect the activity of ERK-1. Compound 2 was evaluated in vivo and showed potent anti-inflammatory effects in two animal models of inflammation, reducing edema formation in the rat carrageenan paw edema assay and paw swelling in the rat adjuvant arthritis model. These findings suggest that inhibitors of cytokine-induced IκBα phosphorylation can exert anti-inflammatory activity in vivo.This study identifies two novel compounds, compound 1 and compound 2, that inhibit the expression of endothelial-leukocyte adhesion molecules (E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) by selectively inhibiting tumor necrosis factor-α (TNFα)-induced phosphorylation of IκB-α. These compounds irreversibly stabilize IκB-α, leading to decreased nuclear translocation of NF-κB and reduced expression of adhesion molecules. Compound 1 also increases the activity of stress-activated protein kinases p38 and JNK-1, but does not affect the activity of ERK-1. Compound 2 was evaluated in vivo and showed potent anti-inflammatory effects in two animal models of inflammation, reducing edema formation in the rat carrageenan paw edema assay and paw swelling in the rat adjuvant arthritis model. These findings suggest that inhibitors of cytokine-induced IκBα phosphorylation can exert anti-inflammatory activity in vivo.