Inhibitors of p38 MAP kinase: therapeutic intervention in cytokine-mediated diseases.
p38 MAP kinase is a member of the family of kinases which mediate intracellular transduction pathways. The activation of this particular MAP kinase pathway is in response to a broad variety of extracellular stimuli. Subsequent downstream events triggered by p38 activation result in the production of IL-1 and TNF-a, suggesting that inhibition of this enzyme may provide a useful therapeutic target for intervention in various diseases mediated by these cytokines. Understanding the biological consequences of p38 activation and inhibition has been the subject of intensive research over the past several years and there is now ample evidence to suggest that inhibition of this enzyme represents a valid approach for target intervention in various cytokine-mediated diseases. Crystal structures of both apo enzyme and enzyme bound to various ligands in conjunction with site specific mutagenesis studies have provided a wealth of information regarding the interactions necessary to result in potent inhibition and selectivity from other kinases. This information has proven useful towards the analysis of previously reported compounds and will provide additional insight towards the design of new compounds and building upon existing SAR.
Salituro
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Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139-4242, USA. Salituro@vpharm.com
Germann
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Wilson
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Bemis
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Fox
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D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D002318:Cardiovascular Diseases / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
C107383:4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases