RESUMEN

5-Carboxamido-1,3,2-dioxaphosphorinanes have been identified as potent inhibitors of microsomal triglyceride-transfer protein. The 1,3,2-dioxaphosphorine functionality acted as a neutral and stable replacement for piperidine and piperidine N-oxide.

Asunto(s)

Amidas/síntesis química , Proteínas Portadoras/antagonistas & inhibidores , Óxidos P-Cíclicos/síntesis química , Amidas/química , Amidas/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Cricetinae , Óxidos P-Cíclicos/química , Óxidos P-Cíclicos/farmacología , Humanos , Técnicas In Vitro , Masculino , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.

Asunto(s)

Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Animales , VLDL-Colesterol/metabolismo , Cricetinae , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas