Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors based on the SAR described herein. Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (17), p.5266-5269
Main Authors: Lacombe, Patrick, Chauret, Nathalie, Claveau, David, Day, Stephen, Deschênes, Denis, Dubé, Daniel, Gallant, Michel, Girard, Yves, Huang, Zheng, Laliberté, France, Lévesque, Jean-Francois, Liu, Susana, Macdonald, Dwight, Mancini, Joseph A., Masson, Paul, Nicholson, Donald W., Nicoll-Griffith, Deborah A., Salem, Myriam, Styhler, Angela, Young, Robert N.
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacokinetics
Aryl Hydrocarbon Hydroxylases - metabolism
Asthma
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Bronchoconstriction
COPD
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
Cytochrome P-450 CYP2C9
Guinea Pigs
Humans
Leukocytes, Mononuclear - metabolism
Medical sciences
Ovalbumin - pharmacology
PDE 4
Pharmacology. Drug treatments
Phosphodiesterase 4 Inhibitors
Phosphodiesterase Inhibitors - chemical synthesis
Phosphodiesterase Inhibitors - chemistry
Phosphodiesterase Inhibitors - pharmacokinetics
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacokinetics
Rats
Respiratory system
Saimiri
Structure-Activity Relationship
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Description
Summary:Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors based on the SAR described herein. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.03.105