Discovery of 6-deoxydapagliflozin as a highly potent sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.
Lingyu
L
Zhang
Yuli
Y
Wang
Huaqiang
H
Xu
Yongheng
Y
Shi
Bingni
B
Liu
Qunchao
Q
Wei
Weiren
W
Xu
Lida
L
Tang
Jianwu
J
Wang
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P.R. China and Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 308 An Shan Xi Dao, Nankai District, Tianjin 300193, P.R. China. zhao_guilong@126.com.
Guilong
G
Zhao
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D003847:Deoxyglucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship
C000593047:1-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1,6-dideoxyglucopyranose; D001559:Benzhydryl Compounds; D001786:Blood Glucose; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D003847:Deoxyglucose