2. Academic Validation
  3. Further Optimization of the mGlu1 PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685

Further Optimization of the mGlu1 PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685

  • ACS Chem Neurosci. 2025 Feb 19;16(4):745-752. doi: 10.1021/acschemneuro.5c00014.
Carson W Reed 1 2,  Jacob F Kalbfleisch 1 2,  Jeremy A Turkett 1 2,  Trevor A Trombley 1 2,  Paul K Spearing 1 2,  Daniel H Haymer 1 2,  Marc Quitalig 1 2,  Jonathan W Dickerson 1 2,  Daniel J Foster 1 2,  Annie L Blobaum 1 2,  Olivier Boutaud 1 2,  Hyekyung P Cho 1 2,  Colleen M Niswender 1 2 3 4 5,  Jerri M Rook 1 2,  Henning Priepke 6,  Heiko Sommer 6,  Stefan Scheuerer 6,  Daniel Ursu 6,  P Jeffrey Conn 1 2 3 4 5,  Bruce J Melancon 1 2,  Craig W Lindsley 1 2 7
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, 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 Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach Germany.
  • 7 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 39907715 DOI: 10.1021/acschemneuro.5c00014
Abstract

Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after the furanyl moiety (a potential toxicophore) was replaced by an N-linked pyrazole, a diversity screen identified a quinoline core, which was further truncated to a pyridine scaffold. PAM VU6033685/BI1752 proved to be a potent and selective mGlu1 PAM with efficacy in both amphetamine-induced hyperlocomotion (AHL) and novel object recognition (NOR) with a clear pharmacokinetic-pharmacodynamic (PK/PD) relationship. VU6024578/BI02982816 was efficacious and well tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited adverse events (AEs) in both rats and dogs. These AEs, noted in two distinct mGlu1 PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.

Keywords

amphetamine-induced hyperlocomotion; cognition; metabolism; metabotropic glutamate receptor subtype 1 (mGlu1); pharmacokinetics; positive allosteric modulator (PAM).

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