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  3. Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies

Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies

  • Eur J Med Chem. 2023 Jan 18;249:115135. doi: 10.1016/j.ejmech.2023.115135.
Dawid Panek 1,  Anna Pasieka 2,  Gniewomir Latacz 3,  Paula Zaręba 2,  Michał Szczęch 2,  Justyna Godyń 2,  Fabien Chantegreil 4,  Florian Nachon 4,  Xavier Brazzolotto 4,  Anna Skrzypczak-Wiercioch 5,  Maria Walczak 6,  Magdalena Smolik 6,  Kinga Sałat 7,  Georg Höfner 8,  Klaus Wanner 8,  Anna Więckowska 2,  Barbara Malawska 2
Affiliations

Affiliations

  • 1 Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Kraków, Poland. Electronic address: dawid.panek@uj.edu.pl.
  • 2 Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Kraków, Poland.
  • 3 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Kraków, Poland.
  • 4 Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223, Brétigny sur Orge, France.
  • 5 Department of Animal Anatomy and Preclinical Sciences, University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Kraków, Poland.
  • 6 Chair and Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St. 9, 30-688, Krakow, Poland.
  • 7 Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Krakow, Poland.
  • 8 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr, 5-13, 81377, Munich, Germany.
PMID: 36696766 DOI: 10.1016/j.ejmech.2023.115135
Abstract

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.

Keywords

Alzheimer's disease; Butyrylcholinesterase; Butyrylcholinesterase inhibitors; Crystallography; Passive avoidance.

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