Discovery of VU0431316: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Bates, Brittney S.^1,2  Rodriguez, Alice L.^1,2  Felts, Andrew S.^1,2  Morrison, Ryan D.^1,2  Venable, Daryl F.^1,2  Blobaum, Anna L.^1,2  Byers, Frank W.^1,2  Lawson, Kera P.^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.2014.06.003

来源: Elsevier

【 摘 要 】

Development of SAR in an aryl ether series of mGlu(5) NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu(5) that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of V1J0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu(5) antagonists and other anxiolytics, produced dose proportional effects. (C) 2014 Elsevier Ltd. All rights reserved.

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