Anti-inflammatory effect and selectivity profile of AS1940477, a novel and potent p38 mitogen-activated protein kinase inhibitor
| Autor: | Tatsuo Inoue, Katsue Magari, Hidekazu Mizuhara, Hitoshi Yamazaki, Masaomi Terajima, Yasuyuki Higashi |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Lipopolysaccharide MAP Kinase Signaling System p38 mitogen-activated protein kinases medicine.medical_treatment Interleukin-1beta Pharmacology p38 Mitogen-Activated Protein Kinases Proinflammatory cytokine Cell Line Substrate Specificity chemistry.chemical_compound Internal medicine Medicine Animals Humans Protein kinase A Protein Kinase Inhibitors Inflammation business.industry Kinase Tumor Necrosis Factor-alpha Anti-Inflammatory Agents Non-Steroidal Rats Endotoxins Pyridazines Cytokine Endocrinology Pyrimidines chemistry Tumor necrosis factor alpha Female business |
| Zdroj: | European journal of pharmacology. 698(1-3) |
| ISSN: | 1879-0712 |
| Popis: | Given the key role p38 mitogen-activated protein kinase (MAPK) plays in inflammatory responses through the production of cytokines and inflammatory mediators, its inhibition is considered a promising therapeutic strategy for chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. Here, we evaluated the anti-inflammatory effect and selectivity profile of the novel p38 MAPK inhibitor AS1940477. AS1940477 inhibited the enzymatic activity of recombinant p38α and β isoforms but showed no effect against other 100 protein kinases including p38γ and δ isoforms. We also confirmed the selectivity of AS1940477 in the intracellular signaling pathway. In human peripheral blood mononuclear cells, AS1940477 inhibited lipopolysaccharide (LPS)- or phytohemagglutinin A (PHA)-induced production of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 at low concentrations (LPS/TNFα, IC 50 =0.45 nM; PHA/TNFα, IC 50 =0.40 nM). In addition, equivalent concentrations of AS1940477 that inhibited cytokine production also inhibited TNFα- and IL-1β-induced production of IL-6, PGE 2 , and MMP-3 in human synovial stromal cells. AS1940477 was also found to potently inhibit TNF production in whole blood (IC 50 =12 nM) and effectively inhibited TNFα production induced by systemically administered LPS in rats at less than 0.1 mg/kg (ED 50 =0.053 mg/kg) with an anti-inflammatory effect lasting for 20 h after oral administration. Overall, this study demonstrated that AS1940477 is a novel and potent p38 MAPK inhibitor and may be useful as a promising anti-inflammatory agent for treating inflammatory disorders. |
| Databáze: | OpenAIRE |
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