Abstract
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 IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha 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.
MeSH terms
-
3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
-
Administration, Oral
-
Animals
-
Arthritis, Infectious / drug therapy
-
Cyclic Nucleotide Phosphodiesterases, Type 4
-
Dogs
-
Female
-
Indoles / chemical synthesis*
-
Indoles / pharmacology
-
Mice
-
Mice, Inbred BALB C
-
Phosphodiesterase Inhibitors / chemical synthesis*
-
Phosphodiesterase Inhibitors / pharmacokinetics
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
Substances
-
Indoles
-
Phosphodiesterase Inhibitors
-
Tumor Necrosis Factor-alpha
-
3',5'-Cyclic-AMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 4