EC50: 18 nM for TNF-α in THP-1 cells
The signal transduction pathway leading to the production of TNF-α from stimulated inflammatory cells, while not fully understood, has been shown to be partially regulated by p38 mitogen activated protein (MAP) kinase. The p38 MAP kinase plays a crucial role in regulating the production of proinflammatory cytokines. Blocking this kinase may offer an effective therapy for the treatment of many inflammatory diseases. BIRB 796 is a highly potent inhibitor of p38 MAPK.
In vitro: BIRB 796 is a picomolar inhibitor of human p38 MAP kinase with a 12,000-fold increase in binding affinity. Moreover, BIRB 796 behavors as one of the most potent and slowest dissociating human p38 MAP kinase inhibitors now known [1].
In vivo: In a LPS-stimulated TNF-α synthesis mouse model, a 65% inhibition of TNF-α synthesis was observed when BIRB 796 was dosed orally at 10 mg/kg. In a model of established collagen-induced arthritis using B10.RIII mice, BIRB 796 showed a 63% inhibition of arthritis severity when dosed orally at 30 mg/kg qd [2].
Clinical trial: No clinical efficacy (Crohn’s Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant and dose-dependent decrease of C-reactive protein level was seen transiently after BIRB 796 after 1 week with a return to baseline level over time [3].
References:
[1] Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol. 2002 Apr;9(4):268-72.
[2] Regan J, Breitfelder S, Cirillo P, Gilmore T, Graham AG, Hickey E, Klaus B, Madwed J, Moriak M, Moss N, Pargellis C, Pav S, Proto A, Swinamer A, Tong L, Torcellini C. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J Med Chem. 2002 Jul 4;45(14):2994-3008.
[3] Schreiber S, Feagan B, D'Haens G, Colombel JF, Geboes K, Yurcov M, Isakov V, Golovenko O, Bernstein CN, Ludwig D, Winter T, Meier U, Yong C, Steffgen J; BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34.