Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Katrina A. Bollinger, Andrew S. Felts, Christopher J. Brassard, Julie L. Engers, Alice L. Rodriguez, Rebecca L. Weiner, Hyekyung P. Cho, Sichen Chang, Michael Bubser, Carrie K. Jones, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Kyle A. Emmitte, Craig W. Lindsley

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.

Original languageEnglish
Pages (from-to)919-924
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number9
DOIs
StatePublished - 2017

Keywords

  • CNS penetration
  • Negative allosteric modulator (NAM)
  • VU6001966
  • depression
  • metabotropic glutamate receptor 2 (mGlu)

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