title: Anti-inflammatory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor.
abstract: We investigated the effects of KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4 (5H)-one) on bronchoconstriction and allergic inflammation in guinea pigs and on tumor necrosis factor-alpha production in mice. KF19514 inhibited phosphodiesterase 4 (IC50 = 0.40 microM) and phosphodiesterase 1 (IC50 = 0.27 microM) derived from canine tracheal smooth muscles. KF19514 relaxed contracted tracheal smooth muscle and had a potent inhibitory effect on antigen-induced bronchoconstriction (EC50 = 0.058 microM) in vitro. Intravenous administration of KF19514 inhibited histamine-induced bronchoconstriction (ID50 = 2.8 microg/kg i.v.). Moreover, oral administration of KF19514 inhibited anaphylactic bronchoconstriction (ID50 = 0.2 mg/kg p.o.), and eosinophil infiltration in airway stimulated with platelet-activating factor (PAF) or antigen. KF19514 also produced a significant inhibition of tumor necrosis factor-alpha production in mice (ID50 = 0.023 mg/kg p.o.). Finally, KF19514 completely inhibited antigen-induced hyperreactivity at 0.1 mg/kg p.o. These results demonstrate that KF19514 may have efficacy in the treatment of asthma.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Manabe
authors.forename: K
authors.initials: K
authors.lastname: Akuta
authors.forename: H
authors.initials: H
authors.lastname: Sejimo
authors.forename: H
authors.initials: H
authors.lastname: Kawasaki
authors.forename: E
authors.initials: E
authors.lastname: Nukui
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
authors.forename: H
authors.initials: H
authors.lastname: Kase
authors.forename: T
authors.initials: T
authors.lastname: Kawakita
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
authors.forename: S
authors.initials: S
authors.lastname: Kitamura
authors.forename: S
authors.initials: S
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Ohmori
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000941:Antigens / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004285:Dogs; D004804:Eosinophils / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006967:Hypersensitivity / Q000276:immunology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009287:Naphthyridines / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000941:Antigens; D001993:Bronchodilator Agents; C106878:KF 19514; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine