2. Academic Validation
  3. Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

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

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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120717
    mGlu2 Negative Allosteric Modulator