Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2201-2205. doi: 10.1016/j.bmcl.2018.04.070. Epub 2018 May 3.

Abstract

The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a-17a) as well as their dehydrate dihydrofuran derivatives (11b-17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules.

Keywords: C-Aryl glucosides; Derivatives; Diabetes; SGLT2 inhibitor; Type-2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Glucosides / chemical synthesis
  • Glucosides / chemistry
  • Glucosides / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Sodium-Glucose Transporter 2 / metabolism*
  • Sodium-Glucose Transporter 2 Inhibitors / chemical synthesis
  • Sodium-Glucose Transporter 2 Inhibitors / chemistry
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Glucosides
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors