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 s...Continue Reading
References
May 7, 1976·Analytical Biochemistry·M M Bradford
Aug 7, 1986·European Journal of Pharmacology·H H SchneiderJ Seidler
Oct 1, 1993·The American Review of Respiratory Disease·P J Barnes, S Pedersen
Apr 12, 1996·Biochemical Pharmacology·M S BarnetteT J Torphy
Jan 1, 1997·The Journal of Allergy and Clinical Immunology·D M EssayanL M Lichtenstein
Oct 6, 1997·American Journal of Respiratory and Critical Care Medicine·E HamelmannE W Gelfand
Feb 26, 1998·American Journal of Respiratory and Critical Care Medicine·T J Torphy
Apr 28, 1999·Neuropharmacology·A RobichaudI W Rodger
Dec 10, 1999·Pulmonary Pharmacology & Therapeutics·F GantnerA Hatzelmann
Mar 8, 2000·International Archives of Allergy and Immunology·I C CrockerR G Townley
Jun 7, 2000·Proceedings of the National Academy of Sciences of the United States of America·G HansenM Conti
Dec 15, 2000·Neuropharmacology·A RobichaudC C Chan
Nov 22, 2001·Brain Research·S LamontagneF Nantel
Jun 8, 2002·Current Pharmaceutical Design·Catherine Burnouf, Marie-Pierre Pruniaux
Apr 22, 2003·The Journal of Pharmacology and Experimental Therapeutics·Yu ZhaoJames M O'Donnell
Sep 18, 2004·Science·James J LeeNancy A Lee
Jan 4, 2006·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·H J KwakH G Cheon
Jul 8, 2008·European Journal of Pharmacology·Hyun Jeong KwakHyae Gyeong Cheon
Sep 2, 2008·The European Respiratory Journal·D R TaylorH K Reddel
Oct 5, 2010·Nature Reviews. Drug Discovery·Leonardo M FabbriPeter Kirkpatrick
Citations
Oct 11, 2014·Drugs·Maria Gabriella MateraMario Cazzola
May 29, 2014·Expert Opinion on Investigational Drugs·Maria Gabriella MateraMario Cazzola
Oct 1, 2015·Expert Opinion on Investigational Drugs·Aaron M MulhallMuhammad A Zafar
Jul 30, 2014·Biomedical Chromatography : BMC·Woon-Ki ChoJin Sook Song
Jan 27, 2019·Expert Opinion on Investigational Drugs·Polyxeni NtontsiGeorgios Hillas
Mar 5, 2021·Scientific Reports·Yung-Che ChenUNKNOWN Taiwan Clinical Trial Consortium of Respiratory Disease (TCORE) group
Apr 30, 2021·PloS One·Won Seok ChoiJi-Yun Lee