title: 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.affiliation: Korea Research Institute of Chemical Technology, Jang-dong 100, Yusung-gu, Daejon, 305-343, Republic of Korea.
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Kwak
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Nam
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Zaesung
authors.initials: Z
authors.lastname: No
authors.forename: Sung Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001249:Asthma / Q000188:drug therapy*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047209:Eosinophil Peroxidase / Q000378:metabolism; D005260:Female; D005289:Ferrets; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C575161:3-(1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl)benzoic acid; D018927:Anti-Asthmatic Agents; D001565:Benzoates; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; D016210:Methacholine Chloride; D010047:Ovalbumin; D047209:Eosinophil Peroxidase