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

Bates BS, Rodriguez AL, Felts AS, Morrison RD, Venable DF, Blobaum AL, Byers FW, Lawson KP, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
Bioorg Med Chem Lett. 2014 24 (15): 3307-14

PMID: 24969015 · PMCID: PMC4090943 · DOI:10.1016/j.bmcl.2014.06.003

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.

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MeSH Terms (16)

Allosteric Site Animals Anxiety Disease Models, Animal Dose-Response Relationship, Drug Drug Discovery Humans Male Mice Molecular Structure Picolinic Acids Pyrazines Rats Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship

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