Journal of medicinal chemistry · 2025
Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.
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Košak Urban, Strašek Benedik Nika, Knez Damijan, Žakelj Simon, Trontelj Jurij, Pišlar Anja, Horvat Selena, Bolje Aljoša, Žnidaršič Neža, Grgurevič Neža, Švara Tanja, Kljun Jakob, Skrzypczak-Wiercioch Anna, Lv Bingbing, Xiong Yucheng, Wang Qinjie, Bian Rui, Shao Jikuan, Dias José, Nachon Florian, Brazzolotto Xavier, Stojan Jure, Sun Haopeng, Sałat Kinga, Gobec Stanislav
Аннотация
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 Aβ1-42-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.