Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin

Bioorg Med Chem. 2014 Feb 15;22(4):1383-93. doi: 10.1016/j.bmc.2013.12.061. Epub 2014 Jan 7.

Abstract

All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.

Keywords: Configuration–activity relationship; DPP-IV inhibitors; Saxagliptin; Stereoisomers; Synthesis.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemical synthesis
  • Adamantane / chemistry
  • Adamantane / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Molecular Docking Simulation
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Dipeptidyl-Peptidase IV Inhibitors
  • saxagliptin
  • Dipeptidyl Peptidase 4
  • Adamantane