Anti-asthmatic effect of ASP3258, a novel phosphodiesterase 4 inhibitor.
ASP3258 is a potent and selective PDE4 inhibitor and exerts a wide-range of anti-inflammatory effects with low emetic potential, a major adverse effect of PDE4 inhibitors. Here, we investigated the anti-asthmatic potency of ASP3258 as compared with those of two representative PDE4 inhibitors: roflumilast and cilomilast. Orally administered ASP3258, roflumilast, and cilomilast all inhibited ovalbumin (OVA)-induced eosinophil infiltration into the airway of sensitized Brown Norway rats with ED(50) values of 0.81, 0.46, and 4.4 mg/kg, respectively. Histological examination also revealed a decreasing trend in inflammatory cell infiltration into the lung following ASP3258 administration. In vitro investigation of bronchodilatory activities showed that these compounds (10(-8)-10(-6) M) concentration-dependently inhibited OVA-induced contraction of trachea isolated from sensitized guinea pigs but had no effect on spasmogen-precontracted tracheal tension prepared from non-sensitized guinea pigs up to 10(-6) M. In vivo experiments using sensitized guinea pigs showed that these orally administered compounds inhibited OVA-induced increases in airway resistance with ED(50) values of 2.2, 0.35, and 12 mg/kg, respectively. Further, orally administered ASP3258 (0.1 and 1 mg/kg), roflumilast (0.1 and 1 mg/kg), and cilomilast (10 mg/kg) significantly suppressed airway hyperresponsiveness caused by OVA exposure. ASP3258's potent inhibition of antigen-induced bronchoconstriction and airway hyperresponsiveness, two characteristic symptoms of bronchial asthma, suggests that this compound will be useful in treating asthma.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. miki.kobayashi@jp.astellas.com
Miki
M
Kobayashi
Satoshi
S
Kubo
Yasuno
Y
Hirano
Seiji
S
Kobayashi
Koichiro
K
Takahashi
Yasuaki
Y
Shimizu
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D009570:Nitriles / Q000494:pharmacology; D010047:Ovalbumin / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014132:Trachea / Q000187:drug effects / Q000502:physiology
C561429:3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid; D000631:Aminopyridines; D018927:Anti-Asthmatic Agents; D001549:Benzamides; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D009287:Naphthyridines; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; C433247:Cilomilast; D010047:Ovalbumin