RESUMO
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed.
Assuntos
Piperazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.
Assuntos
Compostos de Bifenilo/farmacologia , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Naftalenos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Compostos de Bifenilo/síntese química , Canal de Potássio ERG1 , Ergolinas/farmacologia , Humanos , Indicadores e Reagentes , Mianserina/farmacologia , Naftalenos/síntese química , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.