RESUMO
During our effort to design a receptor binding assay to aid in the elucidation of the molecular mechanism of ezetimibe, we prepared a sulfur-35 containing radioligand which exhibits improved potency over the glucuronide conjugate of ezetimibe in both native enterocyte brush border membranes and membranes from cells expressing recombinant NPC1L1. Herein, we describe the different synthetic strategies which were used to obtain this compound as well as its effectiveness in the aforementioned assay.
Assuntos
Anticolesterolemiantes/química , Azetidinas/química , Proteínas de Membrana/antagonistas & inibidores , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Linhagem Celular , Ezetimiba , Glucuronídeos/química , Humanos , Ligantes , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Camundongos , Ligação Proteica , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Radioisótopos de Enxofre/químicaRESUMO
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.
