RESUMEN
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.
Asunto(s)
Isoxazoles/química , Prolina/química , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptor Cannabinoide CB2/agonistas , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Semivida , Humanos , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Ligandos , Masculino , Microsomas Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapéutico , Unión Proteica , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacocinética , Ácido Pirrolidona Carboxílico/uso terapéutico , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Azepinas/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Azepinas/química , Microsomas Hepáticos/metabolismo , Ratas , Ratas WistarRESUMEN
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.