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Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2
Selective analogs of the natural glycoside phloridzin are marketed drugs that reduce
hyperglycemia in diabetes by inhibiting the active sodium glucose cotransporter
SGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as a
target for glycemic control. To expand available type 2 diabetes remedies, we
aimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. We
screened a bioactive compound library for SGLT1 inhibitors and tested primary hits
and additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). Novel
SGLT1/2 inhibitors were discovered in separate chemical clusters of natural and synthetic
compounds. These have IC50‐values in the 10‐100 μmol/L range. The most
potent identified novel inhibitors from different chemical clusters are (SGLT1‐IC50
Mean ± SD, SGLT2‐IC50 Mean ± SD): (+)‐pteryxin (12 ± 2 μmol/L, 9 ± 4 μmol/L), (+)‐ε‐
viniferin (58 ± 18 μmol/L, 110...
Show moreSelective analogs of the natural glycoside phloridzin are marketed drugs that reduce
hyperglycemia in diabetes by inhibiting the active sodium glucose cotransporter
SGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as a
target for glycemic control. To expand available type 2 diabetes remedies, we
aimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. We
screened a bioactive compound library for SGLT1 inhibitors and tested primary hits
and additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). Novel
SGLT1/2 inhibitors were discovered in separate chemical clusters of natural and synthetic
compounds. These have IC50‐values in the 10‐100 μmol/L range. The most
potent identified novel inhibitors from different chemical clusters are (SGLT1‐IC50
Mean ± SD, SGLT2‐IC50 Mean ± SD): (+)‐pteryxin (12 ± 2 μmol/L, 9 ± 4 μmol/L), (+)‐ε‐
viniferin (58 ± 18 μmol/L, 110 μmol/L), quinidine (62 μmol/L, 56 μmol/L), cloperastine
(9 ± 3 μmol/L, 9 ± 7 μmol/L), bepridil (10 ± 5 μmol/L, 14 ± 12 μmol/L), trihexyphenidyl
(12 ± 1 μmol/L, 20 ± 13 μmol/L) and bupivacaine (23 ± 14 μmol/L, 43 ± 29 μmol/L).
The discovered natural inhibitors may be further investigated as new potential (prophylactic)
agents for controlling dietary glucose uptake. The new diverse structure
activity data can provide a starting point for the optimization of novel SGLT1/2 inhibitors
and support the development of virtual SGLT1/2 inhibitor screening models.
Show less- All authors
- Oranje, P.; Gouka, R.; Burggraaff, L.; Vermeer, M.; Chalet, C.; Duchateau, G.; Pijl, P. van der; Geldof, M.; Roo, N. de; Clauwaert, F.; Vanpaeschen, T.; Nicolai, J.; Bruyn, T. de; Annaert, P.; IJzerman, A.P.; Westen, G.J.P. van
- Date
- 2019-08-31
- Volume
- 7
- Issue
- 4
- Pages
- e00504