The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties

Bioorg Med Chem. 2014 Jul 1;22(13):3414-22. doi: 10.1016/j.bmc.2014.04.036. Epub 2014 Apr 28.

Abstract

The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.

Keywords: Canagliflozin; Dapagliflozin; Glucoside; Hydantoin; SGLT2; Triazolopyridinone.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glycosides / chemical synthesis
  • Glycosides / chemistry
  • Glycosides / pharmacology*
  • Humans
  • Molecular Structure
  • Phenytoin / analogs & derivatives*
  • Phenytoin / chemistry
  • Phenytoin / pharmacology
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Glycosides
  • Pyridones
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Triazoles
  • hydroxyphenytoin
  • Phenytoin