Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with a trans-alkene spacer as potent GABA uptake inhibitors

Bioorg Med Chem. 2018 Dec 1;26(22):5944-5961. doi: 10.1016/j.bmc.2018.11.002. Epub 2018 Nov 3.

Abstract

Our study presents the synthesis and structure-activity relationship (SAR) of novel N-substituted nipecotic acid derivatives closely related to DDPM-1457 [(S)-2a], a chemically stable analog of (S)-SNAP-5114 (1), in the pursuit of finding new and potent mGAT4 selective inhibitors. Iminium ion chemistry served as key step for the preparation of the desired, new N-substituted nipecotic acid derivatives containing a variety of different heterocycles attached to the nipecotic acid moiety via a trans-alkene spacer. The target compounds were characterized with regard to their potency at and subtype selectivity for the GABA transporters mGAT1-mGAT4.

Keywords: GABA uptake inhibitor; Hydrozirconation; Iminium ion chemistry; Nipecotic acid; mGAT4.

MeSH terms

  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Dose-Response Relationship, Drug
  • GABA Uptake Inhibitors / chemical synthesis
  • GABA Uptake Inhibitors / chemistry
  • GABA Uptake Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Nipecotic Acids / chemical synthesis
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology*
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Alkenes
  • GABA Uptake Inhibitors
  • Nipecotic Acids
  • nipecotic acid
  • gamma-Aminobutyric Acid