期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 56, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128479
关键词
muscarinic acetylcholine receptor M 4; Spirocycle; Deuterium; cytochrome P450; SAR
资金
- Ancora Innovation, LLC
- DoD [W81XWH-19-1-0355]
- William K. Warren Family and Foundation
This manuscript presents a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as potent antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4), with compound 19 identified as a highly potent and selective antagonist with excellent aqueous solubility and moderate brain exposure in rodents.
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.
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