title: Orally active indole N-oxide PDE4 inhibitors.
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.
authors.affiliation: Rhône-Poulenc Rorer Central Research, Collegeville, PA 19426, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hulme
authors.forename: R
authors.initials: R
authors.lastname: Mathew
authors.forename: K
authors.initials: K
authors.lastname: Moriarty
authors.forename: B
authors.initials: B
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Ramanjulu
authors.forename: P
authors.initials: P
authors.lastname: Cox
authors.forename: J
authors.initials: J
authors.lastname: Souness
authors.forename: K M
authors.initials: KM
authors.lastname: Page
authors.forename: J
authors.initials: J
authors.lastname: Uhl
authors.forename: J
authors.initials: J
authors.lastname: Travis
authors.forename: R
authors.initials: R
authors.lastname: Labaudiniere
authors.forename: F
authors.initials: F
authors.lastname: Huang
authors.forename: S W
authors.initials: SW
authors.lastname: Djuric
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001170:Arthritis, Infectious / Q000188:drug therapy; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D005260:Female; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4