2. Academic Validation
  3. Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate

Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate

  • ACS Chem Neurosci. 2024 Sep 18;15(18):3421-3433. doi: 10.1021/acschemneuro.4c00508.
Julie L Engers 1 2,  Katrina A Bollinger 1 2,  Rory A Capstick 1 2,  Madeline F Long 1 2,  Aaron M Bender 1 2,  Jonathan W Dickerson 1 2,  Weimin Peng 1 2,  Christopher C Presley 1 2,  Hyekyung P Cho 1 2,  Alice L Rodriguez 1 2,  Colleen M Niswender 1 2 3 4 5,  Sean P Moran 1 2,  Zixiu Xiang 1 2,  Anna L Blobaum 1 2,  Olivier Boutaud 1 2,  Jerri M Rook 1 2,  Darren W Engers 1 2,  P Jeffrey Conn 1 2 3,  Craig W Lindsley 1 2 6 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 Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 4 Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 39197083 DOI: 10.1021/acschemneuro.4c00508
Abstract

Herein we report progress toward a backup clinical candidate to the M1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3-b]pyridine-based M1 PAM VU6007477 to isomeric pyrrolo[3,2-b]pyridine and thieno[3,2-b]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2-b]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M1 activation.

Keywords

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

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