Discovery of VU0431316: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

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

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Abstract

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu 5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu 5 antagonists and other anxiolytics, produced dose proportional effects.

Original languageEnglish
Pages (from-to)3307-3314
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number15
DOIs
StatePublished - 1 Aug 2014

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Keywords

  • Allosteric modulator
  • Anxiety
  • CNS
  • Glutamate

Cite this

Bates, B. S., Rodriguez, A. L., Felts, A. S., Morrison, R. D., Venable, D. F., Blobaum, A. L., Byers, F. W., Lawson, K. P., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2014). Discovery of VU0431316: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorganic and Medicinal Chemistry Letters, 24(15), 3307-3314. https://doi.org/10.1016/j.bmcl.2014.06.003