N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors. Issue 10 (15th May 2016)

• Record Type: Journal Article
• Authors: Chu, Kuang-Feng; Yao, Chun-Hsu; Song, Jen-Shin; Chen, Chiung-Tong; Yeh, Teng-Kuang; Hsieh, Tsung-Chih; Huang, Chung-Yu; Wang, Min-Hsien; Wu, Szu-Huei; Chang, Wei-En; Chao, Yu-Sheng; Lee, Jinq-Chyi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 10(2016)
• Page Start: 2242
• Page End: 2250
• Publication Date: 2016-05-15
• Subjects: N-Indolylglycosides -- Sodium-dependent glucose co-transporter -- Structure–activity relationship -- Type 2 diabetes mellitus; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.058
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 derivatives6a and6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that6a and6o 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.