RESUMO
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.
Assuntos
Azepinas/química , Receptor CB2 de Canabinoide/agonistas , Azepinas/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , 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
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.
Assuntos
Morfolinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Inflamação , Camundongos , Modelos Químicos , Estrutura Molecular , Morfolinas/farmacologia , Receptor CB2 de Canabinoide/química , EstereoisomerismoRESUMO
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.