Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer’s Disease

作者：Urban Košak, Nika Strašek Benedik, Damijan Knez, Simon Žakelj, Jurij Trontelj, Anja Pišlar, Selena Horvat, Aljoša Bolje, Neža Žnidaršič, Neža Grgurevič, Tanja Švara, Jakob Kljun, Anna Skrzypczak-Wiercioch, Bingbing Lv, Yucheng Xiong, Qinjie Wang, Rui Bian, Jikuan Shao, José Dias, Florian Nachon, Xavier Brazzolotto, Jure Stojan, Haopeng Sun, Kinga Sałat, Stanislav Gobec · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00577 · 被引用次数：7 · 研究领域：Cholinesterase and Neurodegenerative Diseases、Nicotinic Acetylcholine Receptors Study、Medicinal Plants and Neuroprotection

High Resolution Image Download MS PowerPoint Slide 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.