RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Diseño de Fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos/métodos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
Asunto(s)
Amidas/química , Amidas/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.