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 <b>2</b>, 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 <b>(</b><i>R</i><b>)-(-)-3</b>, 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 <b>2</b>, also in mice with Aβ<sub>1-42</sub>-induced AD-like symptoms. Compound <b>(</b><i>R</i><b>)-(-)-3</b> produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide <b>(</b><i>R</i><b>)-(-)-3</b> an optimized lead compound for alleviating the symptoms of AD.
Authors
- Neža Grgurevič
- Nika Strašek Benedik (ORCID: https://orcid.org/0009-0008-8149-970X)
- Florian Nachon (ORCID: https://orcid.org/0000-0003-0293-2429)
- Xavier Brazzolotto (ORCID: https://orcid.org/0000-0001-9219-1032)
- Stanislav Gobec (ORCID: https://orcid.org/0000-0002-9678-3083)
- Yucheng Xiong (ORCID: https://orcid.org/0000-0002-1714-6773)
- Damijan Knez (ORCID: https://orcid.org/0000-0001-9917-1384)
- Jure Stojan (ORCID: https://orcid.org/0000-0002-6940-0550)
- Haopeng Sun (ORCID: https://orcid.org/0000-0002-5109-0304)
- Jikuan Shao
- Simon Žakelj (ORCID: https://orcid.org/0000-0002-4967-7114)
- José Dias (ORCID: https://orcid.org/0000-0002-7625-0618)
- Jakob Kljun (ORCID: https://orcid.org/0000-0002-1986-4840)
- Jurij Trontelj (ORCID: https://orcid.org/0000-0002-2558-1425)
- Tanja Švara (ORCID: https://orcid.org/0000-0001-5469-9273)
- Aljoša Bolje (ORCID: https://orcid.org/0000-0003-1620-5361)
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Neža Žnidaršič
- Anja Hafner Pišlar (ORCID: https://orcid.org/0000-0002-1159-1024)
- Anna Skrzypczak-Wiercioch (ORCID: https://orcid.org/0000-0003-3057-4278)
- Bingbing Lv (ORCID: https://orcid.org/0000-0001-6829-6555)
- Urban Košak (ORCID: https://orcid.org/0000-0001-7537-0362)
- Qinjie Wang
- Selena Horvat (ORCID: https://orcid.org/0009-0007-2419-6174)
- Rui Bian
Institutions
- Jagiellonian University (PL)
- Nanjing University of Chinese Medicine (CN)
- University of Ljubljana (SI)
- China Pharmaceutical University (CN)
- University of Agriculture in Krakow (PL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00577
- Citations
- 5
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.97
Funders
- Javna Agencija za Raziskovalno Dejavnost RS
- Univerza v Ljubljani
- Ministère des Armées