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 journalArticle

2 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 languageEnglish
Pages (from-to)342-346
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number2
DOIs
StatePublished - 15 Jan 2019

Keywords

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

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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