TPCA-1 is a novel, potent, and selective inhibitor of human IKK-2.
Demonstration that IκB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-κB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis.
In vitro: Determination of the activity of TPCA-1 against ten selected kinases, COX-1 and COX-2, showed the compound to be ~550-fold selective for IKK-2 versus ten of these enzymes. TPCA-1 inhibits lipopolysaccharide-induced human monocyte production of TNF-α, IL-6, and IL-8 with an IC50 of 170 to 320 nM [1].
In vivo: Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg resulted in a dose dependent reduction in the severity of murine collagen-induced arthritis. The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg were comparable to the effects of the antirheumatic drug, etanercept [1].
Clinical trial: No clinical data are available currently.
Reference:
[1] Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Mellor GW, Evans C, Roshak AK. Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3 -thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation. J Pharmacol Exp Ther. 2005 Jan;312(1):373-81.