Therapeutic potential of ASP3258, a selective phosphodiesterase 4 inhibitor, on chronic eosinophilic airway inflammation.

Abstract

We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-α production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an α(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α(2) - adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

• Authors: Miki Kobayashi, Satoshi Kubo, Katsuhisa Shiraki, Masahiro Iwata, Yasuno Hirano, Yoshiaki Ohtsu, Koichiro Takahashi, Yasuaki Shimizu
• Journal: Pharmacology (Pharmacology) Vol. 90 Issue 3-4 Pg. 223-32 ( 2012) ISSN: 1423-0313 [Electronic] Switzerland
• PMID: 23038661 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 S. Karger AG, Basel.

Chemical References

• 3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid
• Interleukin-5
• Naphthyridines
• Phosphodiesterase 4 Inhibitors
• Tumor Necrosis Factor-alpha
• Fibrinogen

Topics

• Animals
• Asthma (blood, drug therapy)
• Bronchial Hyperreactivity (drug therapy)
• Chronic Disease
• Eosinophilia (blood, drug therapy)
• Female
• Fibrinogen (analysis)
• Humans
• Interleukin-5 (biosynthesis)
• Male
• Naphthyridines (therapeutic use)
• Phosphodiesterase 4 Inhibitors (therapeutic use)
• Rats
• Rats, Inbred BN
• Rats, Inbred F344
• Tumor Necrosis Factor-alpha (biosynthesis)