Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.
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.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, ROC.
Chun-Hsu
CH
Yao
Jen-Shin
JS
Song
Chiung-Tong
CT
Chen
Teng-Kuang
TK
Yeh
Ming-Shiu
MS
Hung
Chih-Chun
CC
Chang
Yu-Wei
YW
Liu
Mao-Chia
MC
Yuan
Chieh-Jui
CJ
Hsieh
Chung-Yu
CY
Huang
Min-Hsien
MH
Wang
Ching-Hui
CH
Chiu
Tsung-Chih
TC
Hsieh
Szu-Huei
SH
Wu
Wen-Chi
WC
Hsiao
Kuang-Feng
KF
Chu
Chi-Hui
CH
Tsai
Yu-Sheng
YS
Chao
Jinq-Chyi
JC
Lee
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship; D014994:Xylose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
C562239:4-chloro-3-(4-cyclopropylbenzyl)-1-(xylopyranosyl)-1H-indole; D005960:Glucosides; D007004:Hypoglycemic Agents; D007211:Indoles; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014994:Xylose; D005947:Glucose