Abstract
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
MeSH terms
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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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Aryl Hydrocarbon Hydroxylases / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Cytochrome P-450 CYP2C9
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Guinea Pigs
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Humans
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Leukocytes, Mononuclear / metabolism
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Ovalbumin / 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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Saimiri
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Quinolines
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Ovalbumin
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Cyclic Nucleotide Phosphodiesterases, Type 4