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: Miki Kobayashi, Satoshi Kubo, Masahiro Iwata, Yoshiaki Ohtsu, Koichiro Takahashi, Yasuaki Shimizu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 11 Issue 6 Pg. 732-9 (Jun 2011) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 21315169 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• 3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid
• Adrenergic alpha-2 Receptor Antagonists
• Aminopyridines
• Benzamides
• Cyclohexanecarboxylic Acids
• Cyclopropanes
• Enzyme Inhibitors
• Lipopolysaccharides
• Naphthyridines
• Nitriles
• Tumor Necrosis Factor-alpha
• Roflumilast
• Interleukin-4
• Cilomilast
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Adrenergic alpha-2 Receptor Antagonists (pharmacology)
• Aminopyridines (administration & dosage)
• Animals
• Benzamides (administration & dosage)
• Blood Cells (drug effects, immunology, metabolism, pathology)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Cyclohexanecarboxylic Acids (administration & dosage)
• Cyclopropanes (administration & dosage)
• Enzyme Inhibitors (administration & dosage)
• Ferrets
• Interleukin-4 (metabolism)
• Lipopolysaccharides (immunology, metabolism)
• Macrophages, Alveolar (drug effects, immunology, metabolism, pathology)
• Naphthyridines (administration & dosage)
• Nitriles (administration & dosage)
• Pneumonia (drug therapy, pathology, physiopathology)
• Rats
• Tumor Necrosis Factor-alpha (metabolism)
• Vomiting