ASP3258, an orally active potent phosphodiesterase 4 inhibitor with low emetic activity

• Published in: International immunopharmacology 2011-06, Vol.11 (6), p.732-739
• Main Authors: Kobayashi, Miki, Kubo, Satoshi, Iwata, Masahiro, Ohtsu, Yoshiaki, Takahashi, Koichiro, Shimizu, Yasuaki
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-2 Receptor Antagonists - pharmacology; Airway inflammation; Aminopyridines - administration & dosage; Animals; ASP3258; Benzamides - administration & dosage; Biological and medical sciences; Blood Cells - drug effects; Blood Cells - immunology; Blood Cells - metabolism; Blood Cells - pathology; Bronchoalveolar lavage (BAL); Brown Norway (BN) rat; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Cyclohexanecarboxylic Acids - administration & dosage; Cyclopropanes - administration & dosage; Emesis; Enzyme Inhibitors - administration & dosage; Ferrets; Interleukin-4 - secretion; Lipopolysaccharides - immunology; Lipopolysaccharides - metabolism; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Medical sciences; Mustela; Naphthyridines - administration & dosage; Nitriles - administration & dosage; Pharmacology. Drug treatments; Phosphodiesterase 4 (PDE4); Pneumonia - drug therapy; Pneumonia - pathology; Pneumonia - physiopathology; Rats; Tumor Necrosis Factor-alpha - metabolism; Vomiting
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2011.01.023

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 = 0.28 nM) 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 (3 mg/kg) and cilomilast (10 mg/kg), but not ASP3258 (3 mg/kg), inhibited α 2-adrenoceptor agonist-induced anesthesia in rats and induced emesis in ferrets. Although ASP3258 (3 mg/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.