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Title 

DBM1285 suppresses tumor necrosis factor-alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway

Authors 

Jong Soon KangHwan Mook KimI Y ChoiS B HanYeo Dae YoonHyunju LeeKi Hwan ParkIg Jun ChoChang Woo LeeKiho LeeKi Hoon LeeSong Kyu Park

Publisher 

American Society for Pharmacology and Experimental Therapeutics (ASPET)

Issue Date 

2010

Citation 

Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 2, pp. 657-664

Abstract 

Tumor necrosis factor α(TNF-α) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-α has been considered as a potential therapeutic target for the treatment of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In this study, we report that cyclopropyl-{4-[4-(4-fluorophenyl)-2-piperidin-4-ylthiazol-5-yl]pyrimidin-2-yl} amine (DBM1285) is a novel inhibitor of TNF-α production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-α secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW264.7 cells. However, LPS-induced mRNA expression of TNF-α was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-α production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogenactivated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) signaling pathway. We also confirmed that DBM1285 directly inhibits p38 MAPK enzymatic activity. In vivo administration of DBM1285 inhibited LPS-induced increase in the plasma level of TNF-α in mice. Whole-blood in vivo target inhibition assay also revealed that DBM1285 attenuates p38 MAPK activity after oral administration in mice. Moreover, DBM1285 suppressed zymosan-induced inflammation and adjuvant-induced arthritis in murine models. Collectively, these results suggest that DBM1285 inhibits TNF-α production, at least in part, by blocking the p38 MAPK/MK2 pathway. Furthermore, in vivo results suggest that DBM1285 might be a possible therapeutic candidate for the treatment of TNF-α-related chronic inflammatory diseases.

ISSN 

0022-3565

Link 

http://dx.doi.org/10.1124/jpet.109.161687

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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