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
  • 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.
Products