Abstract
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
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MeSH terms
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Heterocyclic Compounds / chemistry*
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Humans
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Models, Chemical
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Models, Molecular
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Heterocyclic Compounds
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyridines
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Tumor Necrosis Factor-alpha
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, human