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.
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.
School of Pharmacy, Fudan University , 826 Zhangheng Road, Pudong New Area, Shanghai 201203, P. R. China.
Ge
G
Xu
Binhua
B
Lv
Jacques Y
JY
Roberge
Baihua
B
Xu
Jiyan
J
Du
Jiajia
J
Dong
Yuanwei
Y
Chen
Kun
K
Peng
Lili
L
Zhang
Xinxing
X
Tang
Yan
Y
Feng
Min
M
Xu
Wei
W
Fu
Wenbin
W
Zhang
Liangcheng
L
Zhu
Zhongping
Z
Deng
Zelin
Z
Sheng
Ajith
A
Welihinda
Xun
X
Sun
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization
D006027:Glycosides; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors