2. Academic Validation
  3. Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor

Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor

  • Bioorg Med Chem Lett. 2022 Jan 15:56:128479. doi: 10.1016/j.bmcl.2021.128479.
Aaron M Bender 1,  Trever R Carter 2,  Matthew Spock 2,  Alice L Rodriguez 2,  Jonathan W Dickerson 2,  Jerri M Rook 2,  Sichen Chang 2,  Aidong Qi 2,  Christopher C Presley 2,  Darren W Engers 2,  Joel M Harp 3,  Thomas M Bridges 2,  Colleen M Niswender 4,  P Jeffrey Conn 4,  Craig W Lindsley 5
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: aaron.bender@vanderbilt.edu.
  • 2 Warren Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 3 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 4 Warren Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 5 Warren Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: craig.lindsley@vanderbilt.edu.
PMID: 34838649 DOI: 10.1016/j.bmcl.2021.128479
Abstract

In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the Muscarinic Acetylcholine Receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.

Keywords

Deuterium; SAR; Spirocycle; cytochrome P450; muscarinic acetylcholine receptor M(4).

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