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
  • 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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