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

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

doi:10.1016/j.bmcl.2013.09.001

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

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

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27 Scopus citations

Abstract

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 mGlu ₅ 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.

Original language	English
Pages (from-to)	5779-5785
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2013.09.001
State	Published - 1 Nov 2013

Keywords

Allosteric modulator
Anxiety
CNS
Glutamate
mGlu

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Felts, A. S., Rodriguez, A. L., Morrison, R. D., Venable, D. F., Manka, J. T., Bates, B. S., Blobaum, A. L., Byers, F. W., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2013). Discovery of VU0409106: A negative allosteric modulator of mGlu₅ with activity in a mouse model of anxiety. Bioorganic and Medicinal Chemistry Letters, 23(21), 5779-5785. https://doi.org/10.1016/j.bmcl.2013.09.001

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abstract = "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 mGlu 5 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.",

keywords = "Allosteric modulator, Anxiety, CNS, Glutamate, mGlu",

author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Venable, {Daryl F.} and Manka, {Jason T.} and Bates, {Brittney S.} and Blobaum, {Anna L.} and Byers, {Frank W.} and Daniels, {J. Scott} and Niswender, {Colleen M.} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle A.}",

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doi = "10.1016/j.bmcl.2013.09.001",

language = "English",

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Felts, AS, Rodriguez, AL, Morrison, RD, Venable, DF, Manka, JT, Bates, BS, Blobaum, AL, Byers, FW, Daniels, JS, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW & Emmitte, KA 2013, 'Discovery of VU0409106: A negative allosteric modulator of mGlu₅ with activity in a mouse model of anxiety', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 21, pp. 5779-5785. https://doi.org/10.1016/j.bmcl.2013.09.001

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T2 - A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Venable, Daryl F.

AU - Manka, Jason T.

AU - Bates, Brittney S.

AU - Blobaum, Anna L.

AU - Byers, Frank W.

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle A.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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 mGlu 5 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.

AB - 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 mGlu 5 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.

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KW - Anxiety

KW - CNS

KW - Glutamate

KW - mGlu

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

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