Structure-guided design of a brain-penetrant covalent inhibitor of human butyrylcholinesterase with in vivo procognitive efficacy

Mastnak-Sokolov, Peter (avtor), Košak, Urban (avtor), Meden, Anže (avtor), Knez, Damijan (avtor), Žakelj, Simon (avtor), Horvat, Selena (avtor), Pišlar, Anja (avtor), Kljun, Jakob (avtor), Gobec, Stanislav (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: butyrylcholinesterase, BChE, bisnorcymserine, kinetic analyses, Alzheimer’s disease, treatment
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: Str. 22506-22538
• Številčenje: Vol. 69, iss. 19
• PID: 20.500.12556/RUL-189717
• UDK: 615.2:616.894
• ISSN pri članku: 1520-4804
• DOI: 10.1021/acs.jmedchem.6c01737
• COBISS.SI-ID: 294403075
• Datum objave v RUL: 13.10.2026

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: butirilholinesteraza, BChE, bisnorcimserin, kinetična analiza, zdravljenje Alzheimerjeve bolezni, Alzheimerjeva bolezen