Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase

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• 作者：Puneet Chopra ; Onkar Kulkarni ; Shashank Gupta ; Malini Bajpai ; Vijay Kanoje ; Manish Banerjee ; Vimal Bansal ; Senthil Visaga ; Mou Chatterjee ; Tridib Chaira ; Raj Kumar Shirumalla ; Ashwani Kumar Verma ; Sun
• 关键词：MAP kinases ; p38 ; Inflammation ; Arthritis ; Tumor necrosis factor-α ; Interleukin ; Kinases ; Collagen-induced arthritis
• 刊名：International Immunopharmacology
• 出版年：2010
• 出版时间：April 2010
• 年：2010
• 卷：10
• 期：4
• 页码：467-473
• 全文大小：468 K

文摘

The p38 mitogen activated protein kinase (MAPK) is a key signaling molecule that plays a crucial role in the progression of various inflammatory diseases such as rheumatoid arthritis (RA), asthma and chronic obstructive pulmonary disease. The objective of the present study was to evaluate the anti-inflammatory activity of a p38 MAPK inhibitor, AW-814141. AW-814141 inhibited enzymatic activity of recombinant p38-α and β isoforms with IC₅₀ value of 100 nM and 158 nM, respectively. AW-814141 also inhibited the release of tumor necrosis factor (TNF)-α by lipopolysaccharide (LPS) treated human peripheral blood mononuclear cells with an IC₅₀ value of 212 nM and demonstrated selectivity against a panel of few kinases. Oral administration of AW-814141 (10 mpk) in LPS-injected mice resulted in a significant reduction in TNF-α production in the circulation. In a carrageenan-induced rat paw edema model and collagen-induced arthritis model (CIA), AW-814141 dose dependently inhibited paw swelling. In different in vivo efficacy models, efficacy of AW-814141 was found to be better as compared to the reference compounds (Vx-745 and BIRB-796). This study demonstrated that AW-814141 is a novel p38 MAPK inhibitor and it displays promising in vitro and in vivo anti-inflammatory activities and can be used for the treatment of rheumatoid arthritis.