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Bioorg Med Chem ; 28(11): 115457, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32334935

RESUMO

We synthesized and identified four metabolites of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)-1 inhibitor, K-604 (1). Two of the metabolites M1 and M2, were prepared from 1 using a combination reagent of hydrogen peroxide and sodium tungstate with either phosphoric acid or trifluoroethanol as the solvent to control the regioselectivity. Upon exposure of 4b to tert-butyl hypochlorite at -78 °C, the monosulfoxidation afforded synthetic intermediate of M3 in excellent yield. The efficient synthesis of M4 was established. The in vitro metabolic study exhibited a high clearance value (720 µL/min/mg protein) of 1 using human liver microsomes. We orally administered a single dose of 10 mg/kg of 1 to monkeys because the in vitro metabolic patterns are quite similar. Fortunately, the drug concentration of 1 was much higher than those of M1, M2, M3 and M4.


Assuntos
Benzimidazóis/farmacocinética , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/metabolismo , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-Atividade
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