Discovery of VU0409106: A negative allosteric modulator of mGlu₅ with activity in a mouse model of anxiety
2013
Felts, Andrew S. | Rodriguez, Alice L. | Morrison, Ryan D. | Venable, Daryl F. | Manka, Jason T. | Bates, Brittney S. | Blobaum, Anna L. | Byers, Frank W. | Daniels, J Scott | Niswender, Colleen M. | Jones, Carrie K. | Conn, P Jeffrey | Lindsley, Craig W. | Emmitte, Kyle A.
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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