title: N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors.
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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Kuang-Feng
authors.initials: KF
authors.lastname: Chu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Chun-Hsu
authors.initials: CH
authors.lastname: Yao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Hsieh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Min-Hsien
authors.initials: MH
authors.lastname: Wang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Szu-Huei
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Wei-En
authors.initials: WE
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: 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.
authors.forename: Jinq-Chyi
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006027:Glycosides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D006027:Glycosides; D007004:Hypoglycemic Agents; D054852:Small Molecule Libraries; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D005947:Glucose
keywords: N-Indolylglycosides; Sodium-dependent glucose co-transporter; Structure–activity relationship; Type 2 diabetes mellitus