Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct M <sub>4</sub> Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust <i>In Vivo</i> Efficacy
This work describes progress toward an M<sub>4</sub> PAM preclinical candidate. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are detailed within. A novel 1-(7,8-dimethyl-[1,2,4]triazolo[4,3-<i>b</i>]pyridazin-6-yl)piperidin-4-ol scaffold was identified, and optimization provided a highly potent analog <b>VU6025733</b> (hM<sub>4</sub> EC<sub>50</sub> = 23 nM; rM<sub>4</sub> EC<sub>50</sub> = 55 nM). Further characterization revealed a highly selective compound across muscarinic acetylcholine receptor subtypes with exceptional DMPK properties (<i>in vivo</i> rat CL<sub>p</sub> = 5.9 mL/min/kg; <i>t</i><sub>1/2</sub> = 4.8 h; CYP1A2 & CYP2C9 IC<sub>50</sub>s > 30 μM, CYP2D6 IC<sub>50</sub> > 9 μM; CYP3A4 IC<sub>50</sub> > 25 μM). Moreover, <b>VU6025733</b> demonstrated robust <i>in vivo</i> efficacy in a rat amphetamine-induced hyperlocomotion model in a dose-dependent manner. However, hepatotoxicity risk precluded further development.
Authors
- Alison R. Gregro
- Thomas M. Bridges (ORCID: https://orcid.org/0000-0002-0491-4796)
- Jonathan W. Dickerson (ORCID: https://orcid.org/0000-0001-7263-3788)
- Alice L. Rodriguez (ORCID: https://orcid.org/0000-0002-5244-5103)
- Natasha B. Billard
- Kayla J. Temple (ORCID: https://orcid.org/0000-0001-5290-574X)
- Charlotte Park (ORCID: https://orcid.org/0000-0001-7971-1611)
- Darren W. Engers (ORCID: https://orcid.org/0000-0002-3633-3072)
- Logan A. Baker
- Colleen M. Niswender (ORCID: https://orcid.org/0000-0001-6009-8212)
- Katrina A. Bollinger
- Madeline F. Long (ORCID: https://orcid.org/0000-0002-8933-3439)
- Vincent B. Luscombe (ORCID: https://orcid.org/0000-0002-2886-4017)
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Jordan L Cox - O’Neill
- Morten S. Thomsen (ORCID: https://orcid.org/0000-0002-5072-0351)
- Sichen Chang
- Weimin Peng
- Jerri M. Rook
- P. Jeffrey Conn
- Anna E. Ringuette
- Harrie C. M. Boonen
- Craig W. Lindsley
- Thomas Jensen
- Li Peng
Institutions
- Allen Institute for Brain Science (US)
- Lundbeck (Denmark) (DK)
- Vanderbilt University (US)
- Kennedy Center (DK)
- Health Advances (United States) (US)
- Center for Discovery (US)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2026-01-25
- DOI
- https://doi.org/10.1021/acschemneuro.5c00963
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00