Discovery of Canagliflozin, a Novel C-glucoside With Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

J Med Chem. 2010 Sep 9;53(17):6355-60. doi: 10.1021/jm100332n.

Abstract

We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.

MeSH terms

  • Animals
  • Biological Availability
  • Canagliflozin
  • Carbonates / pharmacology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Glucosides / chemical synthesis*
  • Glucosides / pharmacokinetics
  • Glucosides / pharmacology
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology

Substances

  • Carbonates
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • T 1095
  • Thiophenes
  • Canagliflozin