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Publication Abstract from PubMed

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 (IC(50) = 40 nM) with selectivity over AChE and relevant off-targets, including H(1), M(1), alpha(1A) and beta(1) 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 (LC(50) = 2.85 muM) and hERG inhibition (less than 50% at 10 muM). 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.

Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.,Panek D, Pasieka A, Latacz G, Zareba P, Szczech M, Godyn J, Chantegreil F, Nachon F, Brazzolotto X, Skrzypczak-Wiercioch A, Walczak M, Smolik M, Salat K, Hofner G, Wanner K, Wieckowska A, Malawska B Eur J Med Chem. 2023 Mar 5;249:115135. doi: 10.1016/j.ejmech.2023.115135. Epub , 2023 Jan 18. PMID:36696766^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.