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
  • 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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