N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: identification of VU0469650, a potent and selective tool compound with CNS exposure in rats

Bioorg Med Chem Lett. 2013 Jul 1;23(13):3713-8. doi: 10.1016/j.bmcl.2013.05.020. Epub 2013 May 17.

Abstract

Development of SAR in an N-acyl-N'-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects*
  • Animals
  • Central Nervous System / drug effects*
  • Central Nervous System / metabolism
  • Dose-Response Relationship, Drug
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship

Substances

  • Piperazines
  • Receptors, Metabotropic Glutamate
  • VU0469650
  • metabotropic glutamate receptor type 1