Further Optimization of the mGlu<sub>1</sub> PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685
Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu<sub>1</sub>) 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 <i>N</i>-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 mGlu<sub>1</sub> 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 mGlu<sub>1</sub> PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.
Authors
- Jonathan W. Dickerson (ORCID: https://orcid.org/0000-0001-7263-3788)
- Jeremy A. Turkett
- Daniel H. Haymer
- Bruce J. Melancon (ORCID: https://orcid.org/0000-0002-1958-0071)
- Trevor A. Trombley (ORCID: https://orcid.org/0000-0003-0413-0913)
- Daniel Ursu (ORCID: https://orcid.org/0000-0003-3769-0896)
- Hyekyung P. Cho (ORCID: https://orcid.org/0000-0001-5393-2600)
- Stefan Scheuerer (ORCID: https://orcid.org/0000-0002-4417-098X)
- P. Jeffrey Conn (ORCID: https://orcid.org/0000-0003-2363-0323)
- Daniel J. Foster (ORCID: https://orcid.org/0000-0002-5225-354X)
- Jacob F. Kalbfleisch
- Colleen M. Niswender (ORCID: https://orcid.org/0000-0001-6009-8212)
- Henning Priepke
- Carson W. Reed
- Paul K. Spearing
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Jerri M. Rook (ORCID: https://orcid.org/0000-0003-4029-0148)
- Annie L. Blobaum
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Marc Quitalig
- H Sommer
Institutions
- Boehringer Ingelheim (Germany) (DE)
- Vanderbilt University (US)
- Kennedy Center (DK)
- Center for Discovery (US)
- Vanderbilt Health (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1021/acschemneuro.5c00014
- Primary Topic
- Medical Imaging Techniques and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Institute of Mental Health