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
  • 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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