2. Academic Validation
  3. Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

  • ACS Chem Neurosci. 2026 Feb 4;17(3):649-665. doi: 10.1021/acschemneuro.5c00963.
Alison R Gregro 1 2 3,  Charlotte Park 1 2,  Madeline F Long 1 2 3,  Logan A Baker 1 2,  Katrina A Bollinger 1 2,  Anna E Ringuette 1 2,  Li Peng 1 2,  Vincent B Luscombe 1 2,  Natasha B Billard 1 2,  Alice L Rodriguez 1 2 3,  Colleen M Niswender 1 2 4 5 3,  Weimin Peng 2,  Jonathan W Dickerson 2,  Jerri M Rook 2,  Jordan O'Neill 1 2,  Sichen Chang 1 2 3,  Harrie C M Boonen 6,  Thomas Jensen 6,  Morten S Thomsen 6,  Thomas M Bridges 1 2,  Olivier Boutaud 1 2 3,  P Jeffrey Conn 1 2 5,  Darren W Engers 1 2 3,  Craig W Lindsley 1 2 7 8 3,  Kayla J Temple 1 2 3
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 Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, Valby, Copenhagen DK-2500, Denmark.
  • 7 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 8 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 41581069 DOI: 10.1021/acschemneuro.5c00963
Abstract

This work describes progress toward an M4 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-b]pyridazin-6-yl)piperidin-4-ol scaffold was identified, and optimization provided a highly potent analog VU6025733 (hM4 EC50 = 23 nM; rM4 EC50 = 55 nM). Further characterization revealed a highly selective compound across Muscarinic Acetylcholine Receptor subtypes with exceptional DMPK properties (in vivo rat CLp = 5.9 mL/min/kg; t1/2 = 4.8 h; CYP1A2 & CYP2C9 IC50s > 30 μM, CYP2D6 IC50 > 9 μM; CYP3A4 IC50 > 25 μM). Moreover, VU6025733 demonstrated robust in vivo efficacy in a rat amphetamine-induced hyperlocomotion model in a dose-dependent manner. However, hepatotoxicity risk precluded further development.

Keywords

Alzheimer’s disease; M4; Positive allosteric modulator (PAM); muscarinic acetylcholine receptor (mAChR); parkinson’s disease; schizophrenia; structure−activity relationship (SAR).

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