Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy

  • J Med Chem. 2026 Oct 8;69(19):22506-22538. doi: 10.1021/acs.jmedchem.6c01737.
Peter Mastnak-Sokolov  1 ,  Urban Košak  1 ,  Anže Meden  1 ,  Damijan Knez  1 ,  Simon Žakelj  1 ,  Selena Horvat  1 ,  Anja Pišlar  1 ,  Jakob Kljun  2 ,  Alexandre Igert  3 ,  José Dias  3 ,  Florian Nachon  3 ,  Xavier Brazzolotto  3 ,  Martin Novak  4 ,  Vendula Rydlova  4 ,  Jana Zdarova Karasova  5 ,  Ondřej Soukup  4  5 ,  Aleksandra Manik  6 ,  Jan Detka  6 ,  Kinga Sałat  6 ,  Stanislav Gobec
Affiliations
  • 1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000Ljubljana, Slovenia.
  • 2. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 1131000, Ljubljana, Slovenia.
  • 3. Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91220Brétigny sur Orge, France.
  • 4. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska, 581500 05, Hradec Kralove, Czech Republic.
  • 5. Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska, 1575500 01, Hradec Kralove, Czech Republic.
  • 6. Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688Krakow, Poland.
PMID: 42917927 DOI: 10.1021/acs.jmedchem.6c01737
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.

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