Discovery of VU6024578/BI02982816: An mGlu<sub>1</sub> Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models
Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu<sub>1</sub>) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC<sub>50</sub> > 10 μM, 71% Glu<sub>max</sub>), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu<sub>2-5,7,8</sub>) and CNS penetrant (rat K<sub>p</sub> = 0.99, K<sub>p,uu</sub> = 0.82; MDCK-MDR1 ER = 1.7, P<sub>app</sub> = 73 × 10-6 cm/s) mGlu<sub>1</sub> PAM (VU6024578/BI02982816, EC<sub>50</sub> = 54 nM, 83% Glu<sub>max</sub>). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class <i>in vivo</i> rodent tool to study selective mGlu<sub>1</sub> activation.
Authors
- Jonathan W. Dickerson (ORCID: https://orcid.org/0000-0001-7263-3788)
- Mohammad Sarwar (ORCID: https://orcid.org/0000-0002-9569-736X)
- 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)
- Patrizia Voehringer
- 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)
- Niklas Schuelert
- 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
- Anthony F. Nastase
- P. Jeffrey Conn
Institutions
- Boehringer Ingelheim (Germany) (DE)
- Vanderbilt University (US)
- Center for Discovery (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02554
- Citations
- 1
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.27
Funders
- Boehringer Ingelheim
- National Institutes of Health
- National Institute of Mental Health