RESUMEN
In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
Asunto(s)
Azepinas/síntesis química , Hipolipemiantes/síntesis química , Indoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Disponibilidad Biológica , Línea Celular , LDL-Colesterol/sangre , Femenino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Indoles/farmacocinética , Indoles/farmacología , Macaca mulatta , Masculino , Ratones , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ratas , Ratas Sprague-Dawley , Receptores de LDL/genética , Solubilidad , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.