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.
Kimberly M Lovell  1 ,  Andrew S Felts ,  Alice L Rodriguez ,  Daryl F Venable ,  Hyekyung P Cho ,  Ryan D Morrison ,  Frank W Byers ,  J Scott Daniels ,  Colleen M Niswender ,  P Jeffrey Conn ,  Craig W Lindsley ,  Kyle A Emmitte
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 23727046 DOI: 10.1016/j.bmcl.2013.05.020
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.

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