2. Academic Validation
  3. Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs

  • ACS Med Chem Lett. 2017 Aug 15;8(9):925-930. doi: 10.1021/acsmedchemlett.7b00249.
Julie L Engers 1 2,  Katrina A Bollinger 2,  Rebecca L Weiner 2,  Alice L Rodriguez 1 2,  Madeline F Long 2,  Megan M Breiner 2,  Sichen Chang 2,  Sean R Bollinger 2,  Michael Bubser 1 2,  Carrie K Jones 1 2 3,  Ryan D Morrison 2,  Thomas M Bridges 1 2,  Anna L Blobaum 1 2,  Colleen M Niswender 1 2 3,  P Jeffrey Conn 1 2 3,  Kyle A Emmitte 1 2,  Craig W Lindsley 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3 Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
PMID: 28947938 DOI: 10.1021/acsmedchemlett.7b00249
Abstract

Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

Keywords

Negative allosteric modulator (NAM); VU6010572; depression; metabotropic glutamate receptor 3 (mGlu3); physiochemical properties.

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