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.
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 A1, A2b and A3 receptors with IC50 values of 19 +/- 4, 21 +/- 3 and 80 +/- 14 nM, respectively, but also inhibited the p38 mitogen-activated protein (MAP) kinases alpha and beta and the phosphodiesterase 4D (PDE4D) isoenzyme with IC50 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 (IC50 values between 30 and 50 nM) than the standard p38 MAP kinase inhibitor SB203580 (30 nM to >1 microM), the PDE4 inhibitor cilomilast (120-400 nM) and the broad spectrum adenosine receptor antagonist CGS15943 (>10 microM). 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.
Trifilieff
Alexandre
A
Novartis Institutes of BioMedical Research, Respiratory Diseases Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB.
Keller
Thomas H
TH
Press
Neil J
NJ
Howe
Trevor
T
Gedeck
Peter
P
Beer
David
D
Walker
Christoph
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C504066:CGH2466; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D018047:Receptors, Purinergic P1; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; C093642:SB 203580