Abstract
We have identified a novel series of substituted N,N′-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were tested. Among these compounds, 25a inhibited the p38α enzyme with an IC50 value of 0.47 nM and a KD value of 1.54 × 10−8 and appears to be the most promising one in the series.
Highlights
The mitogen-activated protein kinase p38 (p38 MAPK) belongs to the serine/threonine kinase family and plays a major role in the regulation, biosynthesis and actions of key proinflammatory mediators like tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), p53, and mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAPK2), etc. [1]
Previous investigations have indicated that p38α plays an important role in serious diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), psoriasis, and Crohn’s disease [2,3]
We have designed and synthesized a novel series of substituted N,N1 -diarylurea compounds as potential p38α inhibitors and showed that some compounds possessed good inhibitory potencies
Summary
The mitogen-activated protein kinase p38 (p38 MAPK) belongs to the serine/threonine kinase family and plays a major role in the regulation, biosynthesis and actions of key proinflammatory mediators like tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), p53, and mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAPK2), etc. [1]. The mitogen-activated protein kinase p38 (p38 MAPK) belongs to the serine/threonine kinase family and plays a major role in the regulation, biosynthesis and actions of key proinflammatory mediators like tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), p53, and mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAPK2), etc. Previous investigations have indicated that p38α plays an important role in serious diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), psoriasis, and Crohn’s disease [2,3]. Some select candidates are in clinical trials, including losmapimod in phase III for treatment of acute coronary syndrome, LY2228820 in phase II for epithelial ovarian cancer and PH-797804 in phase III for treatment of COPD [9,10,11,12], no p38α inhibitors are currently available on the market. There is continuing need to identify novel bioavailable small molecule inhibitors of p38α
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