RESUMO
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
Assuntos
Isoxazóis/química , Prolina/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptor CB2 de Canabinoide/agonistas , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapêutico , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacocinética , Ácido Pirrolidonocarboxílico/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.
Assuntos
Azepinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Azepinas/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos WistarRESUMO
A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.