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Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N‑(2-(1H‑1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962)

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posted on 04.01.2019, 00:00 by Carson W. Reed, Samantha E. Yohn, Jordan P. Washecheck, Hanna F. Roenfanz, Marc C. Quitalig, Vincent B. Luscombe, Matthew T. Jenkins, Alice L. Rodriguez, Darren W. Engers, Anna L. Blobaum, P. Jeffrey Conn, Colleen M. Niswender, Craig W. Lindsley
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.