Synthetic studies on selective type 4 phosphodiesterase (PDE 4) inhibitors. 1. Structure-activity relationships and pharmacological evaluation of 1,8-naphthyridin-2(1H)-one derivatives.
In order to develop novel and orally active phosphodiesterase (PDE) 4 inhibitors, random screening was performed using our chemical library to find YM-10335 possessing the 1,8-naphthyridin-2(1H)-one skeleton which is a completely different structure from rolipram. In this report, the syntheses and structure-activity relationships of the YM-10335 derivatives were described. Some compounds showed selective inhibitory activities for PDE 4 derived from human peripheral blood cells and no effect on the other PDE types (1, 2, 3, 5). The inhibition of the tumor necrosis factor-alpha (TNF-alpha) release in vitro and the carrageenan-induced pleurisy in rats were also described.
Institute for Drug Discovery Reserch, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan. takaya_k@yamanouchi.co.jp
Kazuhisa
K
Takayama
Masahiro
M
Iwata
Hiroyuki
H
Hisamichi
Yoshinori
Y
Okamoto
Motonori
M
Aoki
Akira
A
Niwa
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002351:Carrageenan / Q000008:administration & dosage; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008297:Male; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010998:Pleurisy / Q000139:chemically induced / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship
D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D002351:Carrageenan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4