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-inflammat ory agents (exemplified by SE-203580) was the human homologue of the stress -induced kinase p38, there has been an explosion of patent literature discl osing related inhibitor analogues. These compounds fall into the general st ructural class of vicinal aryl/pyridin-4-yl heterocycles. Compounds of this class have been claimed as p38 inhibitors or inhibitors of cytokine biosyn thesis. 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 under standable on the basis of recent x-ray crystallographic and mutagenesis stu dies. The inhibitors can be sub-classified based upon a variety of structur al characteristics. Recently new inhibitor structural classes have been dis closed. Although distinctly different structurally, several of these new co mpounds appear to bind with the same key interactions as the vicinal aryl/p yridin-4-yl heterocycles.