Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy
Abstract Butyrylcholinesterase (BChE) has emerged as a validated therapeutic target for the management of Alzheimer’s disease symptoms, particularly in advanced stages when acetylcholinesterase activity declines. Despite the numerous BChE inhibitors reported, only the cymserine derivative bisnorcymserine has progressed to clinical evaluation. Here, we report the design and characterization of a novel selective human BChE (hBChE) inhibitor, N-benzylpyrrolidine carbamate (S)-(+)-14. Kinetic analyses and X-ray crystallography of the hBChE−inhibitor complex confirm a covalent mechanism of inhibition. Compound (S)-(+)-14 demonstrates favorable metabolic stability and achieves brain exposure following intraperitoneal administration in mice. In a scopolamine-induced cognitive impairment model, (S)-(+)-14 improves cognitive performance without causing cholinergic adverse effects or motor deficits. Collectively, these findings identify (S)-(+)-14 as a structurally validated, brain-penetrant covalent hBChE inhibitor and highlight its promise as a lead compound for the treatment of Alzheimer’s disease.
Authors
- Ondřej Soukup (ORCID: https://orcid.org/0000-0001-6376-8701)
- Florian Nachon (ORCID: https://orcid.org/0000-0003-0293-2429)
- Stanislav Gobec (ORCID: https://orcid.org/0000-0002-9678-3083)
- Alexandre Igert (ORCID: https://orcid.org/0000-0002-0421-6488)
- Damijan Knez (ORCID: https://orcid.org/0000-0001-9917-1384)
- Simon Žakelj (ORCID: https://orcid.org/0000-0002-4967-7114)
- José Dias (ORCID: https://orcid.org/0000-0002-7625-0618)
- Jana Žďárová Karasová (ORCID: https://orcid.org/0000-0003-0891-9591)
- Jakob Kljun (ORCID: https://orcid.org/0000-0002-1986-4840)
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Jan Detka (ORCID: https://orcid.org/0000-0002-9866-5777)
- Urban Košak (ORCID: https://orcid.org/0000-0001-7537-0362)
- A. Meden (ORCID: https://orcid.org/0000-0003-3594-6579)
- Aleksandra Manik
- Selena Horvat (ORCID: https://orcid.org/0009-0007-2419-6174)
- Peter Mastnak-Sokolov
- Anja Pišlar (ORCID: https://orcid.org/0000-0002-1159-1024)
- Vendula Rydlová
- Martin Novak
- Xavier Brazzolotto
Institutions
- Jagiellonian University (PL)
- University of Ljubljana (SI)
- Institut de Médecine Tropicale du Service de Santé des Armées (FR)
- University Hospital Hradec Králové (CZ)
- University of Defence (RS)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-09-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01737
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00