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

  • ACS Med Chem Lett. 2017 Aug 3;8(9):919-924. doi: 10.1021/acsmedchemlett.7b00279.
Katrina A Bollinger  1 ,  Andrew S Felts  2  1 ,  Christopher J Brassard  2  1 ,  Julie L Engers  2  1 ,  Alice L Rodriguez  2  1 ,  Rebecca L Weiner  1 ,  Hyekyung P Cho  2  1 ,  Sichen Chang  1 ,  Michael Bubser  2  1 ,  Carrie K Jones  2  1  3 ,  Anna L Blobaum  2  1 ,  Colleen M Niswender  2  1  3 ,  P Jeffrey Conn  2  1  3 ,  Kyle A Emmitte  2  1  4 ,  Craig W Lindsley  2  1  4
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 4. Department of Chemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
PMID: 28947937 DOI: 10.1021/acsmedchemlett.7b00279
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.

Keywords
CNS penetration; Negative allosteric modulator (NAM); VU6001966; depression; metabotropic glutamate receptor 2 (mGlu2).
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