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

Aaron M Bender; Trever R Carter; Matthew Spock; Alice L Rodriguez; Jonathan W Dickerson; Jerri M Rook; Sichen Chang; Aidong Qi; Christopher C Presley; Darren W Engers; Joel M Harp; Thomas M Bridges; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2021.128479

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. Epub 2021 Nov 24.

Authors

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).

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Muscarinic Antagonists / chemical synthesis
Muscarinic Antagonists / chemistry
Muscarinic Antagonists / pharmacology*
Receptor, Muscarinic M4 / antagonists & inhibitors*
Receptor, Muscarinic M4 / metabolism
Structure-Activity Relationship

Substances

Muscarinic Antagonists
Receptor, Muscarinic M4