Bioorganic & medicinal chemistry, 2013-06, Vol.21 (11), p.3154-3163
2013
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Selective CB2 agonists with anti-pruritic activity: Discovery of potent and orally available bicyclic 2-pyridones
- Ist Teil von
- Bioorganic & medicinal chemistry, 2013-06, Vol.21 (11), p.3154-3163
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- Elsevier ScienceDirect Journals
- Beschreibungen/Notizen
- The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0968-0896eISSN: 1464-3391DOI: 10.1016/j.bmc.2013.03.030Titel-ID: cdi_proquest_miscellaneous_1500792984
- Format
- –
- Schlagworte
- Administration, Oral, adverse effects, Agonist, agonists, Animals, Antipruritics - chemical synthesis, Antipruritics - pharmacokinetics, Antipruritics - pharmacology, Behavior, Animal - drug effects, Bridged Bicyclo Compounds - chemical synthesis, Bridged Bicyclo Compounds - pharmacokinetics, Bridged Bicyclo Compounds - pharmacology, Cannabinoid, Cannabinoid CB2 receptors, CB2, chemistry, CHO Cells, Cricetulus, Disease Models, Animal, Drug Discovery, Homology model, Itch, Mice, Mice, Inbred ICR, Molecular Docking Simulation, pain, pharmacokinetics, Pruritus, Pruritus - drug therapy, Pruritus - metabolism, Pruritus - physiopathology, Pyridine-2-one, Pyridone, Pyridones - chemical synthesis, Pyridones - pharmacokinetics, Pyridones - pharmacology, Receptor, Cannabinoid, CB1 - chemistry, Receptor, Cannabinoid, CB2 - agonists, Receptor, Cannabinoid, CB2 - chemistry, Receptor, Cannabinoid, CB2 - metabolism, Structure-Activity Relationship