Inhibitors of p38 MAP kinase: Therapeutic intervention in cytokine-mediated diseases

p38 MAP kinase is a member of the family of kinases which mediate intracell ular transduction pathways. The activation of this particular MAP kinase pa thway is in response to a broad variety of extracellular stimuli. Subsequen t downstream events triggered by p38 activation result in the production of IL-1 and TNF-alpha, suggesting that inhibition of this enzyme may provide a useful therapeutic target for intervention in various diseases mediated b y these cytokines. Understanding the biological consequences of p38 activat ion and inhibition has been the subject of intensive research over the past several years and there is now ample evidence to suggest that inhibition o f this enzyme represents a valid approach for target intervention in variou s cytokine-mediated diseases. Crystal structures of both apo enzyme and enzyme bound to various ligands i n conjunction with site specific mutagenesis studies have provided a wealth of information regarding the interactions necessary to result in potent in hibition and selectivity from other kinases. This information has proven us eful towards the analysis of previously reported compounds and will provide additional insight towards the design of new compounds and building upon e xisting SAR.