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.
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.
Bioorg Med Chem Lett. 2022 Jan 15;56:128479. doi: 10.1016/j.bmcl.2021.128479. Epub 2021 Nov 24.
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 (mAChR). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M 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 M potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.
在本手稿中，我们报告了一系列手性 6-氮杂螺[2.5]辛烷和相关的螺环化合物，它们作为毒蕈碱乙酰胆碱受体亚型 4（mAChR）的高活性和选择性拮抗剂。早期类似物的手性分离和随后的 X 射线晶体学分析表明，R 对映体具有优异的人和大鼠 M 效力，并且对该手性支架的进一步构效关系（SAR）研究导致了发现了 VU6015241（化合物 19）。化合物 19的特点是在多种物种中具有高 M 效力和选择性，在腹腔给药后在啮齿动物中有良好的水溶性和中等的脑暴露。
