Preclinical study demonstrates procognitive effects and enhanced brain exposure of an optimized BChE inhibitor in mouse models of Alzheimer's disease, suggesting therapeutic potential.
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.
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Košak et al. (2025) studied this question.
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