CGH2466, a combined adenosine receptor antagonist, p38 mitogen-activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti-inflammatory activities

Abstract

Theophylline, a phosphodiesterase inhibitor and adenosine receptor antagonist, is used in asthma and chronic obstructive pulmonary disease (COPD) treatment. However, the relatively low effectiveness of theophylline have recently led to reduced usage. The goal of the present study was to identify a theophylline-like compound with improved effectiveness. We discovered CGH2466, which not only antagonised the adenosine A 1, A 2b and A 3 receptors with IC 50 values of 19 ± 4, 21 ± 3 and 80 ± 14 nM, respectively, but also inhibited the p38 mitogen-activated protein (MAP) kinases α and β and the phosphodiesterase 4D (PDE4D) isoenzyme with IC 50 values of 187 ± 18, 400 ± 38 and 22 ± 5 nM, respectively. Despite similar potencies on individual targets, CGH2466 inhibited the production of cytokines and oxygen radicals by human peripheral blood leucocytes in vitro, more potently (IC 50 values between 30 and 50 nM) than the standard p38 MAP kinase inhibitor SB203580 (30 nM to > 1 μM), the PDE4 inhibitor cilomilast (120-400 nM) and the broad spectrum adenosine receptor antagonist CGS15943 (> 10 μM). When given either orally or locally into the lungs, CGH2466 (3 to 10 mg kg -1) inhibited the ovalbumin- or lipopolysaccharide-induced airway inflammation in mice more potently than the single receptor antagonists or enzyme inhibitors used alone. In conclusion, CGH2466 through its combined activities at multiple targets exerted a powerful anti-inflammatory effect and therefore may have beneficial therapeutic value in diseases such as asthma and COPD. © 2005 Nature Publishing Group. All rights reserved.