Abstract
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.
MeSH terms
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Administration, Inhalation
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Humans
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharides / pharmacology
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Phosphodiesterase 4 Inhibitors*
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacokinetics
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Lipopolysaccharides
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Quinolines
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Tumor Necrosis Factor-alpha
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Cyclic Nucleotide Phosphodiesterases, Type 4