化学
体内
药理学
丁酰胆碱酯酶
赫尔格
体外
铅化合物
药代动力学
立体化学
生物化学
酶
阿切
乙酰胆碱酯酶
生物物理学
生物技术
生物
钾通道
医学
作者
Dawid Panek,Anna Pasieka,Gniewomir Latacz,Paula Zaręba,Michał Szczęch,Justyna Godyń,Fabien Chantegreil,Florian Nachon,Xavier Brazzolotto,Anna Skrzypczak-Wiercioch,Maria Walczak,Magdalena Smolik,Kinga Sałat,Georg Höfner,Klaus T. Wanner,Anna Więckowska,Barbara Malawska
标识
DOI:10.1016/j.ejmech.2023.115135
摘要
The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimer's disease. Here, we examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC50 = 40 nM) with selectivity over AChE and relevant off-targets, including H1, M1, α1A and β1 receptors. The compound displays high metabolic stability on human liver microsomes (90% of the parent compound after 2 h of incubation), and its safety was confirmed through examining the cytotoxicity on the HepG2 cell line (LC50 = 2.85 μM) and hERG inhibition (less than 50% at 10 μM). While (rac)-29 lacked an effect in vivo and showed limited penetration to the CNS in pharmacokinetics studies, compound (R)-29 exhibited a procognitive effect at 15 mg/kg in the passive avoidance task in scopolamine-treated mice.
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