The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate

Joseph D. Panarese; Darren W. Engers; Yong Jin Wu; Jason M. Guernon; Aspen Chun; Alison R. Gregro; Aaron M. Bender; Rory A. Capstick; Joshua M. Wieting; Joanne J. Bronson; John E. Macor; Ryan Westphal; Matthew Soars; Julie E. Engers; Andrew S. Felts; Alice L. Rodriguez; Kyle A. Emmitte; Carrie K. Jones; Anna L. Blobaum; P. Jeffrey Conn; Colleen M. Niswender; Corey R. Hopkins; Craig W. Lindsley

doi:10.1016/j.bmcl.2018.10.050

The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu₄ PAM development candidate

Joseph D. Panarese, Darren W. Engers, Yong Jin Wu, Jason M. Guernon, Aspen Chun, Alison R. Gregro, Aaron M. Bender, Rory A. Capstick, Joshua M. Wieting, Joanne J. Bronson, John E. Macor, Ryan Westphal, Matthew Soars, Julie E. Engers, Andrew S. Felts, Alice L. Rodriguez, Kyle A. Emmitte, Carrie K. Jones, Anna L. Blobaum, P. Jeffrey ConnColleen M. Niswender, Corey R. Hopkins, Craig W. Lindsley

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu₄ positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

Original language	English
Pages (from-to)	342-346
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2018.10.050
State	Published - 15 Jan 2019

Keywords

Metabotropic glutamate receptor
Parkinson's disease (PD)
Positive allosteric modulator (PAM)
Structure-activity relationship (SAR)
mGlu

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10.1016/j.bmcl.2018.10.050

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Panarese, J. D., Engers, D. W., Wu, Y. J., Guernon, J. M., Chun, A., Gregro, A. R., Bender, A. M., Capstick, R. A., Wieting, J. M., Bronson, J. J., Macor, J. E., Westphal, R., Soars, M., Engers, J. E., Felts, A. S., Rodriguez, A. L., Emmitte, K. A., Jones, C. K., Blobaum, A. L., ... Lindsley, C. W. (2019). The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu₄ PAM development candidate. Bioorganic and Medicinal Chemistry Letters, 29(2), 342-346. https://doi.org/10.1016/j.bmcl.2018.10.050

Panarese, Joseph D. ; Engers, Darren W. ; Wu, Yong Jin ; Guernon, Jason M. ; Chun, Aspen ; Gregro, Alison R. ; Bender, Aaron M. ; Capstick, Rory A. ; Wieting, Joshua M. ; Bronson, Joanne J. ; Macor, John E. ; Westphal, Ryan ; Soars, Matthew ; Engers, Julie E. ; Felts, Andrew S. ; Rodriguez, Alice L. ; Emmitte, Kyle A. ; Jones, Carrie K. ; Blobaum, Anna L. ; Jeffrey Conn, P. ; Niswender, Colleen M. ; Hopkins, Corey R. ; Lindsley, Craig W. / The discovery of VU0652957 (VU2957, Valiglurax) : SAR and DMPK challenges en route to an mGlu₄ PAM development candidate. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 2. pp. 342-346.

@article{510414c683824ea6aa182511afa46171,

title = "The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate",

abstract = "This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).",

keywords = "Metabotropic glutamate receptor, Parkinson's disease (PD), Positive allosteric modulator (PAM), Structure-activity relationship (SAR), mGlu",

author = "Panarese, {Joseph D.} and Engers, {Darren W.} and Wu, {Yong Jin} and Guernon, {Jason M.} and Aspen Chun and Gregro, {Alison R.} and Bender, {Aaron M.} and Capstick, {Rory A.} and Wieting, {Joshua M.} and Bronson, {Joanne J.} and Macor, {John E.} and Ryan Westphal and Matthew Soars and Engers, {Julie E.} and Felts, {Andrew S.} and Rodriguez, {Alice L.} and Emmitte, {Kyle A.} and Jones, {Carrie K.} and Blobaum, {Anna L.} and {Jeffrey Conn}, P. and Niswender, {Colleen M.} and Hopkins, {Corey R.} and Lindsley, {Craig W.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2019",

month = jan,

day = "15",

doi = "10.1016/j.bmcl.2018.10.050",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Panarese, JD, Engers, DW, Wu, YJ, Guernon, JM, Chun, A, Gregro, AR, Bender, AM, Capstick, RA, Wieting, JM, Bronson, JJ, Macor, JE, Westphal, R, Soars, M, Engers, JE, Felts, AS, Rodriguez, AL, Emmitte, KA, Jones, CK, Blobaum, AL, Jeffrey Conn, P, Niswender, CM, Hopkins, CR & Lindsley, CW 2019, 'The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu₄ PAM development candidate', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 2, pp. 342-346. https://doi.org/10.1016/j.bmcl.2018.10.050

The discovery of VU0652957 (VU2957, Valiglurax) : SAR and DMPK challenges en route to an mGlu₄ PAM development candidate. / Panarese, Joseph D.; Engers, Darren W.; Wu, Yong Jin; Guernon, Jason M.; Chun, Aspen; Gregro, Alison R.; Bender, Aaron M.; Capstick, Rory A.; Wieting, Joshua M.; Bronson, Joanne J.; Macor, John E.; Westphal, Ryan; Soars, Matthew; Engers, Julie E.; Felts, Andrew S.; Rodriguez, Alice L.; Emmitte, Kyle A.; Jones, Carrie K.; Blobaum, Anna L.; Jeffrey Conn, P.; Niswender, Colleen M.; Hopkins, Corey R.; Lindsley, Craig W.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 2, 15.01.2019, p. 342-346.

Research output: Contribution to journal › Article › peer-review

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T1 - The discovery of VU0652957 (VU2957, Valiglurax)

T2 - SAR and DMPK challenges en route to an mGlu4 PAM development candidate

AU - Panarese, Joseph D.

AU - Engers, Darren W.

AU - Wu, Yong Jin

AU - Guernon, Jason M.

AU - Chun, Aspen

AU - Gregro, Alison R.

AU - Bender, Aaron M.

AU - Capstick, Rory A.

AU - Wieting, Joshua M.

AU - Bronson, Joanne J.

AU - Macor, John E.

AU - Westphal, Ryan

AU - Soars, Matthew

AU - Engers, Julie E.

AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Emmitte, Kyle A.

AU - Jones, Carrie K.

AU - Blobaum, Anna L.

AU - Jeffrey Conn, P.

AU - Niswender, Colleen M.

AU - Hopkins, Corey R.

AU - Lindsley, Craig W.

PY - 2019/1/15

Y1 - 2019/1/15

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KW - Parkinson's disease (PD)

KW - Positive allosteric modulator (PAM)

KW - Structure-activity relationship (SAR)

KW - mGlu

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M3 - Article

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AN - SCOPUS:85057471964

VL - 29

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JO - Bioorganic and Medicinal Chemistry Letters

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