Cited by 105Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsEnzyme function and inhibition

Highly Selective Butyrylcholinesterase Inhibitors With Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer’s Disease Mouse Model

Hoffmann, Matthias, Stiller, Carina, Endres, Erik, Scheiner, Matthias, Gunesch, Sandra, Sotriffer, Christoph, Maurice, Tangui, Decker, Michael·2019·Journal of Medicinal Chemistry

Abstract

In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for h BChE over human acetycholinesterase ( h AChE), yielding short-, medium-, and long-acting nanomolar h BChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer’s disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.

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Crossref · 10.1021/acs.jmedchem.9b01012

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84 of 84 references verified0 citation errors · 0 not checkable

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  • During Alzheimer's disease progression, BChE activity can increase significantly, potentially contributing to aggregation of amyloid beta-peptides and formation of senile plaques.

    “Notably, during the progression of AD, BChE activity can increase significantly, potentially contributing to the aggregation of amyloid beta-peptides and the formation of senile plaques, which are characteristic of the disease [90,91].”

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Authors
Hoffmann, M., Stiller, C., Endres, E., Scheiner, M., Gunesch, S., Sotriffer, C., Maurice, T., & Decker, M.
Affiliations
  • University of Würzburg (DE)
  • Inserm (FR)
Corresponding author
Decker, Michael
Venue
Journal of Medicinal Chemistry
Published
2019-10-14
Volume
62
Issue
20
Pages
9116-9140
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2980601903
Cited by
105
References
84
Citations by year
2026: 11 · 2025: 17 · 2024: 18 · 2023: 11 · 2022: 20 · 2021: 14 · 2020: 14
FWCI
8.83
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Bundesministerium f??r Bildung und Forschung
  • Deutscher Akademischer Austauschdienst
  • Campus France
  • Bayerisches Staatsministerium f??r Bildung und Kultus, Wissenschaft und Kunst
  • Deutsche Forschungsgemeinschaft (DE 1546/6-3)
  • Studienstiftung des Deutschen Volkes
Topics
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords
butyrylcholinesterase inhibitors, enzyme selectivity, duration of action, carbamate hydrolysis, binding kinetics, morpholine, tetrahydroisoquinolines, benzimidazole, piperidine, neuroprotection, Alzheimer's disease, disease-modifying therapy, hippocampal cells
MeSH terms
Alzheimer Disease, Animals, Butyrylcholinesterase, Carbamates, Cholinesterase Inhibitors, Disease Models, Animal, Neuroprotective Agents, Mice

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