2. Academic Validation
  3. Discovery of VU6052254: A Novel, Potent M1 Positive Allosteric Modulator

Discovery of VU6052254: A Novel, Potent M1 Positive Allosteric Modulator

  • ACS Chem Neurosci. 2025 Dec 17;16(24):4741-4750. doi: 10.1021/acschemneuro.5c00825.
Julie L Engers 1 2,  Joseph D Bungard 1 2,  Christopher C Presley 1 2,  Irene Zagol-Ikapitte 1 2,  Katherine J Watson 1 2,  Sichen Chang 1 2,  Colin O'Carroll 3,  P Markus Dey 3,  Ethan S Burstein 3,  Jonathan W Dickerson 1 2,  Analisa Thompson Gray 1 2,  Michael Bubser 1 2,  Jerri M Rook 1 2,  Hyekyung P Cho 1 2,  Valerie M Kramlinger 1 2,  Olivier Boutaud 1 2,  Carrie K Jones 1 2,  P Jeffrey Conn 1 2 4,  Darren W Engers 1 2,  Craig W Lindsley 1 2 5 4 6
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 Acadia Pharmaceuticals Inc., San Diego, California 92130, United States.
  • 4 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 41295593 DOI: 10.1021/acschemneuro.5c00825
Abstract

We recently disclosed VU0467319, a Muscarinic Acetylcholine Receptor subtype 1 (M1) Positive Allosteric Modulator (PAM) clinical candidate that had successfully completed a Phase I Single Ascending Dose (SAD) clinical trial, but the identification of an inactive metabolite constituting a major portion of the total plasma AUC detracted from the molecules' pharmacokinetic profile and contributed to clinical development discontinuation. Attempts to block metabolism with the incorporation of deuterium atoms proved successful in vitro and in vivo at low exposures; however, in high-dose nonclinical toxicology studies, the degree of oxidative metabolism and metabolite accumulation was comparable to that of the proteo-congener. Here, we describe a second-generation back-up effort based on the VU0467319 scaffold to discover VU6052254. Strategic placement of a tertiary hydroxyl moiety afforded VU6052254, a potent M1 PAM (EC50 = 59 nM, 79% ACh max), with high CNS exposure (rat Kp = 1.07; Kp,uu = 1.27; P-gp ER = 1.97, Papp = 23 × 10-6 cm/s), reduced metabolism across species, excellent pharmacodynamic responses (MED in rat NOR = 1 mg/kg PO; MED in rat CFC = 0.3 mg/kg PO), excellent multispecies PK (Clps < 10 mL/min/kg, %F > 65), and favorable human PK and dose projections. Based on these beneficial attributes, VU6052254 was nominated for further nonclinical development. However, possible CYP450 induction liability as well as uncertain projected margins for human efficacy at those systemic concentrations where dose/exposure-related clinical and anatomic pathology kidney findings were observed in a 14-day exploratory toxicity study in male rats, precluded further development.

Keywords

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

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