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 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.
Hulme
C
C
Rhône-Poulenc Rorer Central Research, Collegeville, PA 19426, USA.
Mathew
R
R
Moriarty
K
K
Miller
B
B
Ramanjulu
M
M
Cox
P
P
Souness
J
J
Page
K M
KM
Uhl
J
J
Travis
J
J
Labaudiniere
R
R
Huang
F
F
Djuric
S W
SW
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*
D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4