Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes

  • J Med Chem. 2011 Jan 13;54(1):166-78. doi: 10.1021/jm101072y.
Chun-Hsu Yao  1 ,  Jen-Shin Song ,  Chiung-Tong Chen ,  Teng-Kuang Yeh ,  Ming-Shiu Hung ,  Chih-Chun Chang ,  Yu-Wei Liu ,  Mao-Chia Yuan ,  Chieh-Jui Hsieh ,  Chung-Yu Huang ,  Min-Hsien Wang ,  Ching-Hui Chiu ,  Tsung-Chih Hsieh ,  Szu-Huei Wu ,  Wen-Chi Hsiao ,  Kuang-Feng Chu ,  Chi-Hui Tsai ,  Yu-Sheng Chao ,  Jinq-Chyi Lee
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, ROC.
PMID: 21128592 DOI: 10.1021/jm101072y
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.