Article

5a-Carba-β-D-glucopyranose derivatives as novel sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

Research Division, Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
Bioorganic & medicinal chemistry (impact factor: 2.82). 08/2011; 19(18):5334-41. DOI:10.1016/j.bmc.2011.08.005 pp.5334-41
Source: PubMed

ABSTRACT 5a-Carba-β-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.

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Keywords

5a-Carba-β-D-glucopyranose derivatives
 
aglycon structure
 
blood glucose levels
 
db/db mice
 
highest selectivity
 
hypoglycemic action
 
inhibitors exhibited potent SGLT2 inhibition
 
novel SGLT2-selective inhibitors
 
sergliflozin-active
 
tested compounds
 

Yoshihito Ohtake