Discovery of VU6053371/BI03738809: A First-in-Class Selective and CNS-Penetrant mGlu3 Positive Allosteric Modulator (PAM) with Efficacy in a Preclinical Cognition Model

  • ACS Chem Neurosci. 2026 Jun 17;17(12):2406-2418. doi: 10.1021/acschemneuro.6c00325.
Caleb A Jones  1  2 ,  Renn A Duncan  1  2 ,  Kristen M Gilliland  1  2 ,  Carson W Reed  1  2 ,  Daniel H Haymer  1  2 ,  Paul K Spearing  1  2 ,  Rory A Capstick  1  2 ,  Bartholomew P Roland  1  2 ,  Paige Vinson  1  2 ,  Marc Quitalig  1  2 ,  Caroline Baggeroer  1  2 ,  Natasha B Billard  1  2 ,  Jonathan W Dickerson  1  2 ,  Zixiu Xiang  1  2 ,  Valerie M Kramlinger  1  2 ,  Olivier Boutaud  1  2 ,  Julia Schlichtiger  3 ,  Carrie K Jones  1  2 ,  Colleen M Niswender  1  2  4  5 ,  Hyekyung P Cho  1  2 ,  Jerri L Rook  1  2 ,  Carsten T Wotjak  3 ,  Matthias Freiwald  3 ,  Riccardo Giovannini  3 ,  Heiko Sommer  3 ,  Scott Hobson  3 ,  P Jeffrey Conn  1  2 ,  Bruce J Melancon  1  2 ,  Craig W Lindsley  1  2  6
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3. Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany.
  • 4. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 5. Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 42249812 DOI: 10.1021/acschemneuro.6c00325
Abstract

Herein, we report the discovery and development of the first-in-class (FIC), selective, and centrally active metabotropic glutamate receptor subtype 3 (mGlu3) positive allosteric modulator (PAM), VU6053371/BI03738809. A high-throughput screening campaign identified a potent and selective mGlu3 PAM VU6048261/DI013166572 based on a tetra-substituted thiophene core but with poor DMPK properties. Chemical lead optimization efforts managed to dramatically improve protein binding and in vivo rat PK to afford VU6053371/BI03738809. With an FIC in vivo tool compound, VU6053371/BI03738809 demonstrated robust efficacy in rat novel object recognition (NOR) (minimum effective dose (MED) = 3 mg/kg PO) and a clear pharmacokinetic/pharmacodynamic (PK/PD) relationship (PD efficacy observed when free brain concentrations were at, or above, the rat mGlu3 EC50). Thus, selective activation of mGlu3 represents a novel mechanism to address the cognitive impairment associated with schizophrenia (CIAS) and Other neurodegenerative diseases. Moreover, the discovery of VU6053371/BI03738809 completes the group II mGlu receptor toolkit of in vivo PAM and NAM probes for both mGlu2 and mGlu3.

Keywords
cognition; metabolism; metabotropic glutamate receptor subtype 3 (mGlu3); novel object recognition; pharmacokinetics; positive allosteric modulator (PAM).
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