Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1918-22. doi: 10.1016/j.bmcl.2014.03.009. Epub 2014 Mar 12.

Abstract

A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.

Keywords: Aminomethyl-piperidones; Antidiabetic; DPP-IV inhibitors; Long-acting; Selective.

MeSH terms

  • Animals
  • Catalytic Domain
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Drug Design*
  • Enzyme Activation / drug effects*
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Piperidones / chemical synthesis*
  • Piperidones / chemistry
  • Piperidones / pharmacology*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Sitagliptin Phosphate
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Piperidones
  • Pyrazines
  • Triazoles
  • Sitagliptin Phosphate