C-Aryl 5a-carba-beta-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

Article Details

Citation

Ohtake Y, Sato T, Matsuoka H, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Higuchi T, Murakata M, Morikawa K, Shimma N, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S

C-Aryl 5a-carba-beta-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

Bioorg Med Chem. 2012 Jul 1;20(13):4117-27. doi: 10.1016/j.bmc.2012.04.053. Epub 2012 May 4.

PubMed ID
22652255 [ View in PubMed
]
Abstract

C-Aryl 5a-carba-beta-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CanagliflozinSodium/glucose cotransporter 2IC 50 (nM)6.7N/AN/ADetails
DapagliflozinSodium/glucose cotransporter 2IC 50 (nM)1.3N/AN/ADetails