Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5767-71. doi: 10.1016/j.bmcl.2015.10.070. Epub 2015 Oct 30.

Abstract

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.

Keywords: DPP-4 inhibitor; DPP-8; DPP-9; Omarigliptin; Pyrazolopyrolidine; Sitagliptin; Type 2 diabetes; X-ray.

MeSH terms

  • Amides / chemistry*
  • Animals
  • Binding Sites
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
  • Dogs
  • Half-Life
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Pyrans / chemical synthesis
  • Pyrans / chemistry*
  • Pyrans / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*

Substances

  • 2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine
  • Amides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Pyrans
  • Sulfonamides
  • Dipeptidyl Peptidase 4