Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M5 Muscarinic Acetylcholine Receptor

  • J Med Chem. 2024 Aug 22;67(16):14394-14413. doi: 10.1021/acs.jmedchem.4c01193.
Jinming Li  1  2 ,  Douglas L Orsi  1  2 ,  Julie L Engers  1  2 ,  Madeline F Long  1  2 ,  Rory A Capstick  1  2 ,  Mallory A Maurer  1  2 ,  Christopher C Presley  1  2 ,  Paige N Vinson  1  2 ,  Alice L Rodriguez  1  2 ,  Allie Han  1  2 ,  Hyekyung P Cho  1  2 ,  Sichen Chang  1  2 ,  Megan Jackson  1  2 ,  Michael Bubser  1  2 ,  Anna L Blobaum  1  2 ,  Olivier Boutaud  1  2 ,  Michael A Nader  3 ,  Colleen M Niswender  1  2 ,  P Jeffrey Conn  1  2 ,  Carrie K Jones  1  2 ,  Craig W Lindsley  1 ,  Changho Han  1
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 3. Center for the Neurobiology of Addiction Treatment, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, Winston-Salem, North Carolina 27157, United States.
PMID: 39105778 DOI: 10.1021/acs.jmedchem.4c01193
Abstract

While the Muscarinic Acetylcholine Receptor mAChR subtype 5 (M5) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 (45) showed exquisite potency (human M5 IC50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M1-4), desirable brain exposure (Kp = 0.68, Kp,uu = 0.65), and high oral bioavailability (%F > 100%). VU6036864 (45) and its close analogues will support further studies of M5 as advanced antagonist tool compounds and play an important role in the emerging biology of M5.

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