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

Reed CW, Yohn SE, Washecheck JP, Roenfanz HF, Quitalig MC, Luscombe VB, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW
J Med Chem. 2019 62 (3): 1690-1695

PMID: 30608678 · PMCID: PMC6501583 · DOI:10.1021/acs.jmedchem.8b01810

Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.

MeSH Terms (13)

Allosteric Regulation Animals Anti-Anxiety Agents Benzamides Brain Drug Discovery Male Mice, Inbred C57BL Molecular Structure Rats, Sprague-Dawley Receptors, Metabotropic Glutamate Structure-Activity Relationship Triazoles

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