RESUMEN
Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucosa/química , Glucosuria Renal/tratamiento farmacológico , Humanos , Riñón/efectos de los fármacos , Ratas , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 2 de Sodio-GlucosaRESUMEN
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
