Abstract
Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cell Line
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Hydrogen Bonding
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Injections, Intravenous
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / chemistry
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Models, Molecular
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Protein Binding
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Protein Isoforms
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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1-(4-(3-(4-fluorophenyl)-1H-pyrrolo(3,2-b)pyridin-2-yl)pyridin-2-ylamino)propan-2-ol
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Enzyme Inhibitors
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Indoles
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Protein Isoforms
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Pyridines
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Tumor Necrosis Factor-alpha
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases