Novel macrocyclic C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents

Bioorg Med Chem. 2011 Sep 15;19(18):5468-79. doi: 10.1016/j.bmc.2011.07.045. Epub 2011 Jul 28.

Abstract

Novel macrocyclic C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different synthetic routes of macrocyclization were adopted to prepare novel ansa SGLT2 inhibitors. Among the compounds tested, [1,7]dioxacyclopentadecine macrocycles possessing methylthiophenyl at the distal ring 40 or ethoxyphenyl at the distal ring 23 showed the best in vitro inhibitory activity in this series to date (40, IC(50)=0.778 nM and 23, IC(50)=0.899 nM) against hSGLT2.

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cyclization
  • Dose-Response Relationship, Drug
  • Drug Design
  • Glucosides / chemical synthesis
  • Glucosides / chemistry
  • Glucosides / pharmacology*
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Molecular Conformation
  • Sodium-Glucose Transporter 2 / genetics
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Glucosides
  • Hypoglycemic Agents
  • Macrocyclic Compounds
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors