Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition

Sci Rep. 2017 Jul 17;7(1):5581. doi: 10.1038/s41598-017-05895-9.

Abstract

Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbasugars / chemical synthesis*
  • Carbasugars / chemistry
  • Carbasugars / pharmacology
  • Catalysis
  • Diabetes Mellitus, Type 2 / drug therapy
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Palladium / chemistry*
  • Sodium-Glucose Transporter 2 / chemistry*
  • 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

  • Carbasugars
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Palladium