Synthesis and biological evaluation of a series of N-alkylated imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors

Eur J Med Chem. 2016 Nov 29:124:852-880. doi: 10.1016/j.ejmech.2016.09.012. Epub 2016 Sep 7.

Abstract

In this paper, we report the synthesis and biological evaluation of a series of 1,5- and 1,4- substituted derivatives of 1H-imidazol-4-ylacetic acid, a series of 1,2-substituted 3-(1H-imidazol-2-yl)propanoic acid and an N-substituted (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid as new mGAT3 inhibitors. The lipophilic moieties attached to the N-atom of the parent structures were delineated from the 2-[9-(4-methoxyphenyl)-9H-fluoren-9-yl]oxyethyl residue, known from a prototypic mGAT3 inhibitor. For the structure-activity-relationship studies, the spacer between the N-atom of the imidazole ring and the 2-[9-(4-methoxyphenyl)-9H-fluoren-9-yl] moiety was varied in length from three to six atoms, and in nature being either a pure saturated or unsaturated alkyl chain or an alkyl chain containing up to two ether functions. The compounds were characterized for inhibitory potencies at mouse GABA transporter proteins mGAT1-mGAT4. Among the 1,2-substituted compounds, the N-alkylated (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid 12e containing a C5O spacer exhibits a pIC50 value of 5.13 ± 0.04 at mGAT3, but is devoid of significant selectivity for this GABA transporter. However, the inhibitory potency displayed by 12e at mGAT3 nominally surpasses that of SNAP-5294 reported as the most potent inhibitor of mGAT3 so far.

Keywords: GABA uptake; N-alkylimidazolealkanoic acids; mGAT3.

MeSH terms

  • Acyltransferases / antagonists & inhibitors
  • Acyltransferases / metabolism*
  • Alkylation
  • Animals
  • Carboxylic Acids / chemistry
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • GABA Uptake Inhibitors / chemical synthesis*
  • GABA Uptake Inhibitors / chemistry
  • GABA Uptake Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Mice
  • Structure-Activity Relationship

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • GABA Uptake Inhibitors
  • Imidazoles
  • Acyltransferases
  • 2-acylglycerol O-acyltransferase