Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.
Development of SAR in an aryl ether series of mGlu5 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 mGlu5 antagonists as well as clinically efficacious anxiolytics.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Andrew S
AS
Felts
Alice L
AL
Rodriguez
Ryan D
RD
Morrison
Daryl F
DF
Venable
Jason T
JT
Manka
Brittney S
BS
Bates
Anna L
AL
Blobaum
Frank W
FW
Byers
J Scott
JS
Daniels
Colleen M
CM
Niswender
Carrie K
CK
Jones
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
Kyle A
KA
Emmitte
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001549:Benzamides; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; C577470:VU0409106
Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5)