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

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

  • Bioorg Med Chem. 2016 May 15;24(10):2242-50. doi: 10.1016/j.bmc.2016.03.058.
Kuang-Feng Chu 1,  Chun-Hsu Yao 1,  Jen-Shin Song 1,  Chiung-Tong Chen 1,  Teng-Kuang Yeh 1,  Tsung-Chih Hsieh 1,  Chung-Yu Huang 1,  Min-Hsien Wang 1,  Szu-Huei Wu 1,  Wei-En Chang 1,  Yu-Sheng Chao 1,  Jinq-Chyi Lee 2
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
  • 2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan. Electronic address: jinqchyi@nhri.org.tw.
PMID: 27075813 DOI: 10.1016/j.bmc.2016.03.058
Abstract

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.

Keywords

N-Indolylglycosides; Sodium-dependent glucose co-transporter; Structure–activity relationship; Type 2 diabetes mellitus.

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