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Panek, Dawid; Pasieka, Anna; Latacz, Gniewomir; Zaręba, Paula; Szczęch, Michał; Godyń, Justyna; Chantegreil, Fabien; Nachon, Florian; Brazzolotto, Xavier; Skrzypczak-Wiercioch, Anna; Walczak, Maria; Smolik, Magdalena; Sałat, Kinga; Höfner, Georg; Wanner, Klaus; Więckowska, Anna; Malawska, Barbara
European journal of medicinal chemistry, 03/2023, Volume: 249Journal Article
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. Display omitted •Series of novel potential anti-Alzheimer's agents were designed and synthesized.•Highly potent and selective inhibitors of hBuChE were discovered with 3-(cyclohexylmethyl)amino-2-hydroxypropyl chemotype.•Crystal structures of hBChE in complex with new selected inhibitors were solved.•In vitro ADME-tox, in vivo pharmacokinetic and pharmacodynamic studies were performed.
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