Substituted 1,8-naphthyridin-2(1H)-ones as selective phosphodiesterase IV inhibitors.
New substituted 1,8-naphthyridin-2(1H)-ones have been found to exhibit highly selective phosphodiesterase (PDE) IV inhibition. These compounds inhibited polymorphonuclear leukocyte activation induced by N-formylmethionyl-leucyl-phenylalanine and caused relaxation of isolated guinea pig trachea precontracted by histamine or leukotriene D4. In anesthetized guinea pigs, presensitized with the antigen, these compounds also alleviated airway constriction induced by the antigen. Since these compounds differ in their chemical structure compared with theophylline and other PDE IV inhibitors so far reported and some of them have been shown to be well tolerated in acute toxicity studies, they will provide a new tool for investigating the possible relationship between PDE IV inhibition and anti-asthmatic activity.
Matsuura
A
A
Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
Ashizawa
N
N
Asakura
R
R
Kumonaka
T
T
Aotsuka
T
T
Hase
T
T
Shimizu
C
C
Kurihara
T
T
Kobayashi
F
F
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D000941:Antigens / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects
D000941:Antigens; D007527:Isoenzymes; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4