1. Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.
- Author
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Yao CH, Song JS, Chen CT, Yeh TK, Hung MS, Chang CC, Liu YW, Yuan MC, Hsieh CJ, Huang CY, Wang MH, Chiu CH, Hsieh TC, Wu SH, Hsiao WC, Chu KF, Tsai CH, Chao YS, and Lee JC
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental urine, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 urine, Glucose metabolism, Glucosides pharmacokinetics, Glucosides pharmacology, Humans, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents pharmacology, Indoles pharmacokinetics, Indoles pharmacology, Male, Mice, Mice, Inbred ICR, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Xylose chemical synthesis, Xylose pharmacokinetics, Xylose pharmacology, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Type 2 drug therapy, Glucosides chemical synthesis, Hyperglycemia drug therapy, Hypoglycemic Agents chemical synthesis, Indoles chemical synthesis, Sodium-Glucose Transporter 2 Inhibitors, Xylose analogs & derivatives
- Abstract
A novel series of N-linked β-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-(β-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.
- Published
- 2011
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