20.500.12556/RUL-176545 Lead optimization of a butyrylcholinesterase inhibitor for the treatment of Alzheimer’s disease Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer’s disease (AD). We have recently developed lead compound 2, a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound (R)-(−)-3, a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound 2, also in mice with Aβ$_{1−42}$-induced AD-like symptoms. Compound (R)-(−)-3 produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide (R)-(−)-3 an optimized lead compound for alleviating the symptoms of AD. central nervous system drug discovery inhibitors screening assays sulfones centralni živčni sistem odkrivanje zdravil inhibitorji presejalni testi sulfoni Alzheimerjeva bolezen zdravljenje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-12-03 13:27:35 2025-12-03 13:27:40 2025-12-22 04:01:45 0000-00-00 00:00:00 2025 0 0 Str. 11693-11723 iss. 11 Vol. 68 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894 1520-4804 10.1021/acs.jmedchem.5c00577 238259203 kosak-et-al-2025-lead-optimization-of-a-butyrylcholinesterase-inhibitor-for-the-treatment-of-alzheimer-s-disease.pdf kosak-et-al-2025-lead-optimization-of-a-butyrylcholinesterase-inhibitor-for-the-treatment-of-alzheimer-s-disease.pdf 1 8635E96299A5EB66383D8617280CFB0F 03e79b13af20e8497bae9999ebee6ede505e8807221db87320fafdfff6b15efb 63879907-d043-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=222939 https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00577 1 12f63724-d043-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=222938 Fakulteta za farmacijo Veterinarska fakulteta Fakulteta za kemijo in kemijsko tehnologijo Medicinska fakulteta 0 0 0