20.500.12556/RUL-189717 Structure-guided design of a brain-penetrant covalent inhibitor of human butyrylcholinesterase with in vivo procognitive efficacy 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. butyrylcholinesterase BChE bisnorcymserine kinetic analyses Alzheimer’s disease treatment butirilholinesteraza BChE bisnorcimserin kinetična analiza zdravljenje Alzheimerjeve bolezni Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2026-10-13 15:23:07 2026-10-13 15:23:13 2026-10-14 04:14:06 0000-00-00 00:00:00 2026 0 0 Str. 22506-22538 iss. 19 Vol. 69 Oct. 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616.894 1520-4804 10.1021/acs.jmedchem.6c01737 294403075 jm6c01737.pdf jm6c01737.pdf 1 403CDAC3DDD87E43DC45E2A07C030CDE 5b1e7447c5094427d5d0f4f91317b661ee9176fd43109f56855989ad41d3a6be 0780b96a-c70a-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250472 https://pubs.acs.org/jmcmar/article/69/19/22506/5439005/Structure-Guided-Design-of-a-Brain-Penetrant 0 5b7b8e40-c709-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250471 Fakulteta za farmacijo Fakulteta za kemijo in kemijsko tehnologijo 0 0 0