| Publication Type |
Journal Article |
| Title |
Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation |
| Authors |
Ana R. Jesus Diogo Vila-Vicosa Miguel Machuqueiro Ana P. Marques Timothy M. Dore Amélia P. Rauter |
| Groups |
HC |
| Journal |
JOURNAL OF MEDICINAL CHEMISTRY |
| Year |
2017 |
| Month |
January |
| Volume |
60 |
| Number |
2 |
| Pages |
568-579 |
| Abstract |
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. |
| DOI |
http://dx.doi.org/10.1021/acs.jmedchem.6b01134 |
| ISBN |
|
| Publisher |
|
| Book Title |
|
| ISSN |
0022-2623 |
| EISSN |
1520-4804 |
| Conference Name |
|
| Bibtex ID |
ISI:000393009500003 |
| Observations |
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