Abstract
A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-α production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-α release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).
Highlights
The p38 mitogen-activated protein kinase (p38MAPK) plays a key role in inflammatory responses through the production of cytokines and inflammatory mediators such as TNF-α and IL-1β [1]
P38MAPKα inhibitors, like many other kinase inhibitors, can be classified into two types based on their mode of action: ATP-competitive inhibitors, which bind to an ATP-binding site, and non-ATP-competitive or allosteric inhibitors
Because the allosteric pocket is less conserved than the ATP binding region, allosteric inhibitors usually have better kinase selectivity profiles than ATP competitive inhibitors [8]
Summary
The p38 mitogen-activated protein kinase (p38MAPK) plays a key role in inflammatory responses through the production of cytokines and inflammatory mediators such as TNF-α and IL-1β [1]. Recent studies have revealed that p38MAPKα inhibitors may have therapeutic potential in the treatment of cancer [4,5], neuropathic pain [6] and periodontal diseases [7]. P38MAPKα inhibitors, like many other kinase inhibitors, can be classified into two types based on their mode of action: ATP-competitive inhibitors, which bind to an ATP-binding site, and non-ATP-competitive or allosteric inhibitors. Allosteric inhibitors utilize the ATP binding cleft and a hydrophobic allosteric pocket created when the activation loop adopts the inactive “Asp-Phe-Gly (DFG)-out” conformation. Because the allosteric pocket is less conserved than the ATP binding region, allosteric inhibitors usually have better kinase selectivity profiles than ATP competitive inhibitors [8]. BIRB796 is a typical allosteric p38MAPKα inhibitor with an N-pyrazole-N'-naphthyl urea scaffold. The crystal structure of the p38MAPKα/BIRB796 complex shows that BIRB796 fits well into the DFG-out conformation by forming several tight interactions.
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