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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090943 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2014.06.003 | DOI Listing |
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