2. Academic Validation
  3. Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease

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

  • J Med Chem. 2025 Jun 12;68(11):11693-11723. doi: 10.1021/acs.jmedchem.5c00577.
Urban Košak 1,  Nika Strašek Benedik 1,  Damijan Knez 1,  Simon Žakelj 1,  Jurij Trontelj 1,  Anja Pišlar 1,  Selena Horvat 1,  Aljoša Bolje 1,  Neža Žnidaršič 2,  Neža Grgurevič 2,  Tanja Švara 3,  Jakob Kljun 4,  Anna Skrzypczak-Wiercioch 5,  Bingbing Lv 6,  Yucheng Xiong 6,  Qinjie Wang 7,  Rui Bian 6,  Jikuan Shao 6,  José Dias 8,  Florian Nachon 8,  Xavier Brazzolotto 8,  Jure Stojan 9,  Haopeng Sun 6,  Kinga Sałat 10,  Stanislav Gobec 1
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
  • 2 Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000 Ljubljana, Slovenia.
  • 3 Institute of Pathology, Wild Animals, Fish and Bees, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000 Ljubljana, Slovenia.
  • 4 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
  • 5 University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, 24/28 Mickiewicza St., 30-059 Krakow, Poland.
  • 6 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • 7 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China.
  • 8 Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91220 Brétigny sur Orge, France.
  • 9 Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
  • 10 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
PMID: 40454648 DOI: 10.1021/acs.jmedchem.5c00577
Abstract

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.

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