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

[Display omitted] 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 generati...

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Published in:Bioorganic & medicinal chemistry letters 2022-01, Vol.56, p.128479-128479, Article 128479
Main Authors: Bender, Aaron M., Carter, Trever R., Spock, Matthew, Rodriguez, Alice L., Dickerson, Jonathan W., Rook, Jerri M., Chang, Sichen, Qi, Aidong, Presley, Christopher C., Engers, Darren W., Harp, Joel M., Bridges, Thomas M., Niswender, Colleen M., Conn, P. Jeffrey, Lindsley, Craig W.
Format: Article
Language:English
Subjects:
cytochrome P450
Deuterium
muscarinic acetylcholine receptor M4
SAR
Spirocycle
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2021.128479