New inhibitors of p38 kinase

In the short time since the 1994 report that the molecular target for the 4-aryl-5-pyridin-4-yl imidazole class of cytokine suppressive anti-inflammatory agents (exemplified by SB-203580) was the human homologue of the stress-induced kinase p38, there has been an explosion of patent literature disclosing related inhibitor analogues. These compounds fall into the general structural class of vicinal aryl/pyridin-4-yl heterocycles. Compounds of this class have been claimed as p38 inhibitors or inhibitors of cytokine biosynthesis. Since cytokines mediate a variety of disease processes, inhibition of cytokine biosynthesis has potential as a therapeutic target. The SAR of binding to p38 for this intensively studied class of compounds is now understandable on the basis of recent x-ray crystallographic and mutagenesis studies. The inhibitors can be sub-classified based upon a variety of structural characteristics. Recently new inhibitor structural classes have been disclosed. Although distinctly different structurally, several of these new compounds appear to bind with the same key interactions as the vicinal aryl/pyridin-4-yl heterocycles.

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