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Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M5 Muscarinic Acetylcholine Receptor.
Li, Jinming; Orsi, Douglas L; Engers, Julie L; Long, Madeline F; Capstick, Rory A; Maurer, Mallory A; Presley, Christopher C; Vinson, Paige N; Rodriguez, Alice L; Han, Allie; Cho, Hyekyung P; Chang, Sichen; Jackson, Megan; Bubser, Michael; Blobaum, Anna L; Boutaud, Olivier; Nader, Michael A; Niswender, Colleen M; Conn, P Jeffrey; Jones, Carrie K; Lindsley, Craig W; Han, Changho.
Afiliação
  • Li J; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Orsi DL; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Engers JL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Long MF; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Capstick RA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Maurer MA; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Presley CC; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Vinson PN; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Rodriguez AL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Han A; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Cho HP; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Chang S; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Jackson M; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Bubser M; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Blobaum AL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Boutaud O; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Nader MA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Niswender CM; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Conn PJ; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Jones CK; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Lindsley CW; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • Han C; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
J Med Chem ; 67(16): 14394-14413, 2024 Aug 22.
Article em En | MEDLINE | ID: mdl-39105778
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridinas / Receptor Muscarínico M5 Limite: Animals / Humans Idioma: En Revista: J Med Chem Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridinas / Receptor Muscarínico M5 Limite: Animals / Humans Idioma: En Revista: J Med Chem Ano de publicação: 2024 Tipo de documento: Article