The discovery of VU0652957 (VU2957, Valiglurax)

SAR and DMPK challenges en route to an mGlu 4 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 Allen Emmitte, Carrie K. Jones, Anna L. Blobaum, P. Jeffrey Conn & 3 others Colleen M. Niswender, Corey R. Hopkins, Craig W. Lindsley

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 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 languageEnglish
Pages (from-to)342-346
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number2
DOIs
StatePublished - 15 Jan 2019

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Modulators

Keywords

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

Cite this

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 Allen ; 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 mGlu 4 PAM development candidate. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 2. pp. 342-346.
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abstract = "This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 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 Allen} and Jones, {Carrie K.} and Blobaum, {Anna L.} and {Jeffrey Conn}, P. and Niswender, {Colleen M.} and Hopkins, {Corey R.} and Lindsley, {Craig W.}",
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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 mGlu 4 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 mGlu 4 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 Allen; 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 journalArticleResearchpeer-review

TY - JOUR

T1 - The discovery of VU0652957 (VU2957, Valiglurax)

T2 - SAR and DMPK challenges en route to an mGlu 4 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 Allen

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

N2 - This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 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).

AB - This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 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).

KW - Metabotropic glutamate receptor

KW - Parkinson's disease (PD)

KW - Positive allosteric modulator (PAM)

KW - Structure-activity relationship (SAR)

KW - mGlu

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U2 - 10.1016/j.bmcl.2018.10.050

DO - 10.1016/j.bmcl.2018.10.050

M3 - Article

VL - 29

SP - 342

EP - 346

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 2

ER -