期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 2, 页码 568-579出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01134
关键词
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资金
- European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration [612347]
- Fundacao para a Ciencia e a Tecnologia (FCT) [UID/MULTI/00612/2013]
- BPD fellowship [SFRH/BPD/110491/2015]
- [SFRH/BD/78236/2011]
- [REDE/1.501/REM/2005]
Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10-19 mu M). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.
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