Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu 7 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)

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 a...

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Veröffentlicht in:	Journal of medicinal chemistry 2019-02, Vol.62 (3), p.1690-1695
Hauptverfasser:	Reed, Carson W, Yohn, Samantha E, Washecheck, Jordan P, Roenfanz, Hanna F, Quitalig, Marc C, Luscombe, Vincent B, Jenkins, Matthew T, Rodriguez, Alice L, Engers, Darren W, Blobaum, Anna L, Conn, P Jeffrey, Niswender, Colleen M, Lindsley, Craig W
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation Animals Anti-Anxiety Agents - chemical synthesis Anti-Anxiety Agents - chemistry Anti-Anxiety Agents - pharmacology Benzamides - chemical synthesis Benzamides - chemistry Benzamides - pharmacology Brain - metabolism Drug Discovery Male Mice, Inbred C57BL Molecular Structure Rats, Sprague-Dawley Receptors, Metabotropic Glutamate - metabolism Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology
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Beschreibung
Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.8b01810