RESUMO
Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 µM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 µM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Monossacarídeos/farmacologia , Oximas/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Administração Intravenosa , Administração Oral , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glucose/análise , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Estrutura Molecular , Monossacarídeos/química , Oximas/administração & dosagem , Oximas/química , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio , Relação Estrutura-AtividadeRESUMO
A novel series of N-linked ß-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(ß-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
