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.


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.

MeSH terms

  • Animals
  • Cyclization
  • Glycosides / chemical synthesis
  • Glycosides / chemistry*
  • Glycosides / pharmacokinetics
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Male
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Spiro Compounds / chemistry*


  • Glycosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Spiro Compounds