Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 20, Pages 9116-9140Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01012
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Funding
- German Research Council (Deutsche Forschungsgemeinschaft) under DFG [DE 1546/6-3]
- Campus France (PHC Procope)
- German Academic Exchange Service (DAAD)
- Federal Ministry of Education and Research (BMBF)
- German Academic National Foundation (Studienstiftung des deutschen Volkes)
- International Doctoral Program Receptor Dynamics of the Elite Network of Bavaria (Elitenetzwerk Bayern)
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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 hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE 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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