Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu3 NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2670-2674. doi: 10.1016/j.bmcl.2019.07.030.
Yosuke Yamada  1 ,  Samantha E Yohn  2 ,  Kristen Gilliland  1 ,  Mathew T Loch  1 ,  Michael L Schulte  2 ,  Alice L Rodriguez  2 ,  Anna L Blobaum  2 ,  Colleen M Niswender  3 ,  P Jeffrey Conn  3 ,  Craig W Lindsley  4
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
  • 3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 31358468 DOI: 10.1016/j.bmcl.2019.07.030
Abstract

This letter describes the further optimization of a series of mGlu3 NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (CA2+ flux via a promiscuous G protein (Gα15) versus native coupling to GIRK channels), identified both full and partial mGlu3 NAMs and a new in vivo tool compound, VU6017587. This mGlu3 NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice.

Keywords
Metabotropic glutamate receptor; Negative allosteric modulator (NAM); Structure-Activity Relationship (SAR); mGlu(3).