Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Daryl F. Venable, Jason T. Manka, Brittney S. Bates, Anna L. Blobaum, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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Abstract

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu 5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.

Original languageEnglish
Pages (from-to)5779-5785
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number21
DOIs
StatePublished - 1 Nov 2013

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Keywords

  • Allosteric modulator
  • Anxiety
  • CNS
  • Glutamate
  • mGlu

Cite this

Felts, A. S., Rodriguez, A. L., Morrison, R. D., Venable, D. F., Manka, J. T., Bates, B. S., Blobaum, A. L., Byers, F. W., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2013). Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorganic and Medicinal Chemistry Letters, 23(21), 5779-5785. https://doi.org/10.1016/j.bmcl.2013.09.001