2. Academic Validation
  3. Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials

Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials

  • ACS Chem Neurosci. 2025 Jan 1;16(1):95-107. doi: 10.1021/acschemneuro.4c00769.
Michael S Poslunsey 1 2,  Michael R Wood 1 2,  Changho Han 1 2,  Shaun R Stauffer 1 2,  Joseph D Panarese 1 2,  Bruce J Melancon 1 2,  Julie L Engers 1 2,  Jonathan W Dickerson 1 2,  Weimin Peng 1 2,  Meredith J Noetzel 1 2,  Hyekyung P Cho 1 2,  Alice L Rodriguez 1 2,  Corey R Hopkins 1 2,  Ryan Morrison 1 2,  Rachel D Crouch 1 2,  Thomas M Bridges 1 2,  Anna L Blobaum 1 2,  Olivier Boutaud 1 2,  J Scott Daniels 1 2,  Michael J Kates 3,  Arlindo Castelhano 3,  Jerri M Rook 1 2,  Colleen M Niswender 1 2 4 5 6,  Carrie K Jones 1 2,  P Jeffrey Conn 1 2 4,  Craig W Lindsley 1 2 7 4
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 Davos Pharma, Upper Saddle River, New Jersey 07458, United States.
  • 4 Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 7 Department of Chemistry, Vanderbilt University, Nashville Tennessee 37232, United States.
PMID: 39660766 DOI: 10.1021/acschemneuro.4c00769
Abstract

Herein we detail the first disclosure of VU0467319 (VU319), an M1 Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 (16) is a moderately potent M1 PAM (M1 PAM EC50 = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M1 agonism (EC50 > 30 μM), that displayed high CNS penetration (Kps > 0.67 and Kp,uus > 0.9) and multispecies pharmacokinetics permissive of further development. Based on robust efficacy in multiple preclinical models of cognition, an ancillary pharmacology profile devoid of appreciable off-target activities, and a lack of cholinergic adverse effects (AEs) in rats, dogs and nonhuman primates, VU319 advanced into IND-enabling studies. After completing 4-week rat and dog GLP toxicology without AEs, including absence of cholinergic effects, the first in human Phase I SAD clinical trial of VU319 (NCT03220295) was performed at Vanderbilt, where a similar lack of adverse effects, including absence of cholinergic effects was noted. Moreover, signals of target engagement were seen at the highest dose tested. Thus, VU319 demonstrated the feasibility of achieving selective targeting of central M1 muscarinic receptors without eliciting cholinergic AEs that have plagued Other drugs targeting CNS cholinergic neurotransmission.

Keywords

cognition; metabolism; muscarinic acetylcholine receptor subtype 1 (M1); positive allosteric modulator (PAM).

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