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INFLAMMATION AND IMMUNOPHARMACOLOGY

Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent, Selective Small Molecule Inhibitor of IB Kinase 2, TPCA-1 (2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation

Respiratory and Inflammation Center of Excellence for Drug Discovery (P.L.P., J.F.C., B.J.B., Y.H.L., K.C., T.G.D.), Systems Research (G.W.M), Drug Metabolism and Pharmacokinetics (C.E.), and Project and Portfolio Management (A.K.R.), GlaxoSmithKline, King of Prussia, Pennsylvania

Demonstration that IB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-B-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)- and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC₅₀ = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-, IL-6, and IL-8 with an IC₅₀ = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1, IL-6, TNF-, and interferon-, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.

Address correspondence to: Dr. Patricia Podolin, GlaxoSmithKline, Mail Code UW2532, 709 Swedeland Road, King of Prussia, PA 19406. E-mail: patty_podolin{at}gsk.com

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