C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.
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Robinson RP, Mascitti V, Boustany-Kari CM, Carr CL, Foley PM, Kimoto E, Leininger MT, Lowe A, Klenotic MK, Macdonald JI, Maguire RJ, Masterson VM, Maurer TS, Miao Z, Patel JD, Preville C, Reese MR, She L, Steppan CM, Thuma BA, Zhu T
C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1569-72. doi: 10.1016/j.bmcl.2010.01.075. Epub 2010 Jan 21.
- PubMed ID
- 20149653 [ View in PubMed]
- Abstract
Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Dapagliflozin Sodium/glucose cotransporter 2 IC 50 (nM) 1.4 N/A N/A Details