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

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3307-14. doi: 10.1016/j.bmcl.2014.06.003.
Brittney S Bates  1 ,  Alice L Rodriguez  1 ,  Andrew S Felts  1 ,  Ryan D Morrison  1 ,  Daryl F Venable  1 ,  Anna L Blobaum  1 ,  Frank W Byers  1 ,  Kera P Lawson  1 ,  J Scott Daniels  1 ,  Colleen M Niswender  1 ,  Carrie K Jones  2 ,  P Jeffrey Conn  1 ,  Craig W Lindsley  3 ,  Kyle A Emmitte  4
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212, USA.
  • 3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 24969015 DOI: 10.1016/j.bmcl.2014.06.003
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 mGlu5 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 mGlu5 antagonists and Other anxiolytics, produced dose proportional effects.

Keywords
Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5).
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