Selective analogs of the natural glycoside phloridzin are marketed drugs that reducehyperglycemia in diabetes by inhibiting the active sodium glucose cotransporterSGLT2 in the kidneys. In addition,... Show moreSelective analogs of the natural glycoside phloridzin are marketed drugs that reducehyperglycemia in diabetes by inhibiting the active sodium glucose cotransporterSGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as atarget for glycemic control. To expand available type 2 diabetes remedies, weaimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. Wescreened a bioactive compound library for SGLT1 inhibitors and tested primary hitsand additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). NovelSGLT1/2 inhibitors were discovered in separate chemical clusters of natural and syntheticcompounds. These have IC50‐values in the 10‐100 μmol/L range. The mostpotent identified novel inhibitors from different chemical clusters are (SGLT1‐IC50Mean ± 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 structureactivity data can provide a starting point for the optimization of novel SGLT1/2 inhibitorsand support the development of virtual SGLT1/2 inhibitor screening models. Show less
