Orally active indole N-oxide PDE4 inhibitors

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC 50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-α l...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-11, Vol.8 (21), p.3053-3058
Main Authors: Hulme, Christopher, Mathew, Rose, Moriarty, Kevin, Miller, Bruce, Ramanjulu, Mercy, Cox, Paul, Souness, John, Page, Ken M., Uhl, Joanne, Travis, Jeffrey, Labaudiniere, Richard, Huang, Fu-chih, Djuric, Stevan W.
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Administration, Oral
Animals
Arthritis, Infectious - drug therapy
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cyclic Nucleotide Phosphodiesterases, Type 4
Dogs
Female
Indoles - chemical synthesis
Indoles - pharmacology
Medical sciences
Mice
Mice, Inbred BALB C
Pharmacology. Drug treatments
Phosphodiesterase Inhibitors - chemical synthesis
Phosphodiesterase Inhibitors - pharmacokinetics
Tumor Necrosis Factor-alpha - antagonists & inhibitors
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Summary:This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC 50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-α levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00572-1