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

Kimberly M. Lovell, 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

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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.

Original languageEnglish
Pages (from-to)3713-3718
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number13
DOIs
StatePublished - 1 Jul 2013

Keywords

  • Allosteric modulator
  • CNS
  • GPCR mGlu
  • Glutamate
  • Piperazine

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    Lovell, K. M., Felts, A. S., Rodriguez, A. L., Venable, D. F., Cho, H. P., Morrison, R. D., Byers, F. W., Daniels, J. S., Niswender, C. M., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2013). N-Acyl-N′-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats. Bioorganic and Medicinal Chemistry Letters, 23(13), 3713-3718. https://doi.org/10.1016/j.bmcl.2013.05.020