title: ASP3258, an orally active potent phosphodiesterase 4 inhibitor with low emetic activity.
abstract: We investigated the pharmacology of a novel phosphodiesterase (PDE) 4 inhibitor, ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), comparing its potency with that of the most advanced PDE4 inhibitors, roflumilast and cilomilast. PDE4 inhibition by ASP3258 (IC(50)=0.28nM) was as potent as that achieved with roflumilast. ASP3258 inhibited lipopolysaccharide-induced tumor necrosis factor (TNF)-α production in rat whole blood cells (IC(50)=8.8 nM) and rat alveolar macrophages (IC(50)=2.6 nM). Orally administered ASP3258, roflumilast, and cilomilast dose-dependently inhibited production of interleukin-4, TNF-α, and cysteinyl leukotrienes, as well as leukocyte infiltration in bronchoalveolar lavage fluid from the airways of ovalbumin-sensitized Brown Norway rats, and these compounds showed almost complete inhibition at doses of 3, 3, and 30 mg/kg, respectively. PDE4 inhibitors induce emesis by mimicking the pharmacological action of α(2)-adrenoceptor antagonist. However, orally administered roflumilast (3mg/kg) and cilomilast (10mg/kg), but not ASP3258 (3mg/kg), inhibited α(2)-adrenoceptor agonist-induced anesthesia in rats and induced emesis in ferrets. Although ASP3258 (3mg/kg) inhibited airway inflammation completely, it had no emetic activity. As such, this compound may be useful in treating airway inflammatory diseases such as asthma and COPD.
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwata
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ohtsu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D001773:Blood Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage; D003521:Cyclopropanes / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005289:Ferrets; D015847:Interleukin-4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009287:Naphthyridines / Q000008:administration & dosage; D009570:Nitriles / Q000008:administration & dosage; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014839:Vomiting
chemical_list: C561429:3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid; D058669:Adrenergic alpha-2 Receptor Antagonists; D000631:Aminopyridines; D001549:Benzamides; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009287:Naphthyridines; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D015847:Interleukin-4; C433247:Cilomilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4