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

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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 mGlu5 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.

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Acknowledgements

We thank NIDA (RO1 DA023947) and Seaside Therapeutics (VUMC33842) for their support of our programs in the development of noncompetitive antagonist of mGlu5. We also thank Tammy S. Santomango for technical contributions with the protein binding assays.

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      VU0409106, VU0366058 and VU0366248 represent chemotypes distinct from MPEP – namely the aryl ether series (Felts et al., 2013), 5-cyanopyrimides (Mueller et al., 2012) and 3-cyano-5-fluoro-N-arylbenzamides (Felts et al., 2010) respectively. Previous reports indicate VU0409106 and VU0366058 are full NAMs of glutamate-mediated iCa2+ mobilization, while VU0366248 is a partial NAM (Felts et al., 2013; Gregory et al., 2012). Fenobam and dipraglurant were included to represent mGlu5 NAMs that have progressed to clinical trials (Pecknold et al., 1982; Tison et al., 2016).

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