Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 11, Issue 6, Pages 732-739Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2011.01.023
Keywords
ASP3258; Phosphodiesterase 4 (PDE4); Bronchoalveolar lavage (BAL); Brown Norway (BN) rat; Airway inflammation; Emesis
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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 add), 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 A5P3258 inhibited lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha 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-alpha, 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 alpha(2)-adrenoceptor antagonist. However, orally administered roflumilast (3 mg/kg) and cilomilast (10 mg/kg), but not A5P3258 (3 mg/kg), inhibited a2-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. (C) 2011 Elsevier BM. All rights reserved.
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