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

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

doi:10.1016/j.bmcl.2014.06.003

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

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

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Abstract

Development of SAR in an aryl ether series of mGlu₅ 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 VU0431316 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.

Original language	English
Pages (from-to)	3307-3314
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2014.06.003
State	Published - 1 Aug 2014

Keywords

Allosteric modulator
Anxiety
CNS
Glutamate

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Bates, B. S., Rodriguez, A. L., Felts, A. S., Morrison, R. D., Venable, D. F., Blobaum, A. L., Byers, F. W., Lawson, K. P., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2014). Discovery of VU0431316: A negative allosteric modulator of mGlu₅ with activity in a mouse model of anxiety. Bioorganic and Medicinal Chemistry Letters, 24(15), 3307-3314. https://doi.org/10.1016/j.bmcl.2014.06.003

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

abstract = "Development of SAR in an aryl ether series of mGlu5 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 VU0431316 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.",

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

author = "Bates, {Brittney S.} and Rodriguez, {Alice L.} and Felts, {Andrew S.} and Morrison, {Ryan D.} and Venable, {Daryl F.} and Blobaum, {Anna L.} and Byers, {Frank W.} and Lawson, {Kera P.} 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.2014.06.003",

language = "English",

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Bates, BS, Rodriguez, AL, Felts, AS, Morrison, RD, Venable, DF, Blobaum, AL, Byers, FW, Lawson, KP, Daniels, JS, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW & Emmitte, KA 2014, 'Discovery of VU0431316: A negative allosteric modulator of mGlu₅ with activity in a mouse model of anxiety', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 15, pp. 3307-3314. https://doi.org/10.1016/j.bmcl.2014.06.003

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

AU - Bates, Brittney S.

AU - Rodriguez, Alice L.

AU - Felts, Andrew S.

AU - Morrison, Ryan D.

AU - Venable, Daryl F.

AU - Blobaum, Anna L.

AU - Byers, Frank W.

AU - Lawson, Kera P.

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 - 2014/8/1

Y1 - 2014/8/1

N2 - Development of SAR in an aryl ether series of mGlu5 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 VU0431316 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.

AB - Development of SAR in an aryl ether series of mGlu5 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 VU0431316 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.

KW - Allosteric modulator

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KW - CNS

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

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