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

Bioorg Med Chem. 2019 Mar 1;27(5):822-831. doi: 10.1016/j.bmc.2019.01.024. Epub 2019 Jan 24.

Abstract

To discover new, potent, and selective inhibitors for the murine gamma-aminobutyric acid transporter 4 (mGAT4), the structure-activity relationship (SAR) study of a new cis-alkene analog family based on DDPM-1457 [(S)-2], which previously showed promising inhibitory potency at and subtype selectivity for mGAT4, was conducted. To uncover the importance of the differences between the trans- and the cis-alkene moiety in the spacer, the present publication describes the synthesis of the new compounds via catalytic hydrogenation with Lindlar's catalyst. The biological results collected by the SAR study revealed that analog rac-7j characterized by a four-instead of a three-carbon atom spacer with a cis double bond applying to the majority of the studied compounds displays a surprisingly high potency at mGAT1 (pIC50 = 6.00 ± 0.04) and at the same time a reasonable potency at mGAT4 (pIC50 = 4.82).

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Animals
  • Drug Design
  • GABA Plasma Membrane Transport Proteins / metabolism
  • GABA Uptake Inhibitors / chemical synthesis
  • GABA Uptake Inhibitors / chemistry
  • GABA Uptake Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Nipecotic Acids / chemical synthesis
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tiagabine / pharmacology

Substances

  • Alkenes
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Gabt4 protein, mouse
  • Nipecotic Acids
  • Tiagabine