N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors

被引：22

作者：

Chu, Kuang-Feng ^{[1
]}

Yao, Chun-Hsu ^{[1
]}

Song, Jen-Shin ^{[1
]}

Chen, Chiung-Tong ^{[1
]}

Yeh, Teng-Kuang ^{[1
]}

Hsieh, Tsung-Chih ^{[1
]}

Huang, Chung-Yu ^{[1
]}

Wang, Min-Hsien ^{[1
]}

Wu, Szu-Huei ^{[1
]}

Chang, Wei-En ^{[1
]}

Chao, Yu-Sheng ^{[1
,2
]}

Lee, Jinq-Chyi ^{[1
]}

机构：

[1] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, 35 Keyan Rd, Zhunan Town 35053, Miaoli County, Taiwan

[2] Diamond BioFund INC, 5F,3,Sect 1,Dunhua S Rd, Taipei 105, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 10期

关键词：

N-Indolylglycosides; Sodium-dependent glucose co-transporter; Structure-activity relationship; Type 2 diabetes mellitus; 1ST GLOBAL APPROVAL; NA+/GLUCOSE COTRANSPORTER; GALACTOSE MALABSORPTION; SGLT2; INHIBITORS; TERMINAL ALKYNES; DAPAGLIFLOZIN; 30-50-PERCENT; TRAFFICKING; MECHANISM; TRANSPORT;

D O I：

10.1016/j.bmc.2016.03.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2242 / 2250

页数：9

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