Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes

Ge Xu; Binhua Lv; Jacques Y Roberge; Baihua Xu; Jiyan Du; Jiajia Dong; Yuanwei Chen; Kun Peng; Lili Zhang; Xinxing Tang; Yan Feng; Min Xu; Wei Fu; Wenbin Zhang; Liangcheng Zhu; Zhongping Deng; Zelin Sheng; Ajith Welihinda; Xun Sun

doi:10.1021/jm401780b

Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes

J Med Chem. 2014 Feb 27;57(4):1236-51. doi: 10.1021/jm401780b. Epub 2014 Feb 12.

Affiliation

¹ School of Pharmacy, Fudan University , 826 Zhangheng Road, Pudong New Area, Shanghai 201203, P. R. China.

PMID: 24456245
DOI: 10.1021/jm401780b

Abstract

SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while retaining similar in vitro inhibitory activities against hSGLT2. In particular, deuterated compound 41 has the potential to be a robust long-acting antidiabetic agent.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2 / drug therapy*
Glycosides / chemical synthesis
Glycosides / chemistry*
Glycosides / pharmacology*
Magnetic Resonance Spectroscopy
Rats
Rats, Sprague-Dawley
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors*
Spectrometry, Mass, Electrospray Ionization

Substances

Glycosides
SLC5A2 protein, human
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors