Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model.

Abstract

Phosphodiesterase-4 (PDE-4) is responsible for metabolizing adenosine 3',5'-cyclic monophosphate that reduces the activation of a wide range of inflammatory cells including eosinophils. PDE-4 inhibitors are under development for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Herein, we report a novel PDE-4 inhibitor, PDE-423 (3-[1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid), which shows good in vitro and in vivo oral activities. PDE-423 exhibited in vitro IC(50)s of 140 nM and 550 nM in enzyme assay and cell-based assay, respectively. In vivo study using ovalbumin-induced asthmatic mice revealed that PDE-423 reduced methacholine-stimulated airway hyperreactivity in a dose-dependent manner by once daily oral administration (ED(50)=18.3 mg/kg), in parallel with decreased eosinophil peroxidase activity and improved lung histology. In addition, PDE-423 was effective in diminishing lipopolysaccharide-induced neutrophilia in vivo as well as in vitro. Oral administration of PDE-423 (100 mg/kg) had no effect on the duration of xylazine/ketamine-induced anesthesia and did not induce vomiting incidence in ferrets up to the dose of 1000 mg/kg. The present study indicates that a novel PDE-4 inhibitor, PDE-423, has good pharmacological profiles implicating this as a potential candidate for the development of a new anti-asthmatic drug.

• Authors: Hyun Jeong Kwak, Ji Yeon Nam, Jin Sook Song, Zaesung No, Sung Don Yang, Hyae Gyeong Cheon
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 685 Issue 1-3 Pg. 141-8 (Jun 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22554769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• 3-(1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl)benzoic acid
• Anti-Asthmatic Agents
• Benzoates
• Lipopolysaccharides
• Phosphodiesterase 4 Inhibitors
• Pyrazoles
• Methacholine Chloride
• Ovalbumin
• Eosinophil Peroxidase

Topics

• Administration, Oral
• Animals
• Anti-Asthmatic Agents (administration & dosage, pharmacology, toxicity)
• Asthma (drug therapy)
• Benzoates (administration & dosage, pharmacology, toxicity)
• Bronchial Hyperreactivity (drug therapy, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Eosinophil Peroxidase (metabolism)
• Female
• Ferrets
• Guinea Pigs
• Inhibitory Concentration 50
• Lipopolysaccharides (toxicity)
• Male
• Methacholine Chloride
• Mice
• Mice, Inbred BALB C
• Ovalbumin
• Phosphodiesterase 4 Inhibitors (administration & dosage, pharmacology, toxicity)
• Pyrazoles (administration & dosage, pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley