RESUMEN
A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.
Asunto(s)
Azepinas/química , Receptor Cannabinoide CB2/agonistas , Azepinas/farmacología , Células CACO-2 , Permeabilidad de la Membrana Celular , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , 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
Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.
Asunto(s)
Morfolinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Inflamación , Ratones , Modelos Químicos , Estructura Molecular , Morfolinas/farmacología , Receptor Cannabinoide CB2/química , EstereoisomerismoRESUMEN
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.