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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 1998-11, Vol.8 (21), p.3053-3058
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Beschreibung
Zusammenfassung:	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