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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Felts, Andrew S.^1,2  Rodriguez, Alice L.^1,2  Morrison, Ryan D.^1,2  Venable, Daryl F.^1,2  Manka, Jason T.^1,2  Bates, Brittney S.^1,2  Blobaum, Anna L.^1,2  Byers, Frank W.^1,2  Daniels, J. Scott^1,2  Niswender, Colleen M.^1,2  Jones, Carrie K.^1,2,4  Conn, P. Jeffrey^1,2  Lindsley, Craig W.^1,2,3  Emmitte, Kyle A.^1,2,3 

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA

关键词: Glutamate;    CNS;    mGlu(5);    Allosteric modulator;    Anxiety;   

DOI  :  10.1016/j.bmcl.2013.09.001

来源: Elsevier

【 摘 要 】

Development of SAR in an aryl ether series of mGlu(5) 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 mGlu(5) antagonists as well as clinically efficacious anxiolytics. (c) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

Free