The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity

  • J Med Chem. 2018 Jan 11;61(1):119-139. doi: 10.1021/acs.jmedchem.7b01086.
Urban Košak  1 ,  Boris Brus  1 ,  Damijan Knez  1 ,  Simon Žakelj  1 ,  Jurij Trontelj  1 ,  Anja Pišlar  1 ,  Roman Šink  1 ,  Marko Jukič  1 ,  Marko Živin  2 ,  Adrian Podkowa  3 ,  Florian Nachon  4 ,  Xavier Brazzolotto  4 ,  Jure Stojan  5 ,  Janko Kos  1 ,  Nicolas Coquelle  6 ,  Kinga Sałat  3 ,  Jacques-Philippe Colletier  6 ,  Stanislav Gobec  1
Affiliations
  • 1. Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
  • 2. Institute of Pathological Physiology, Faculty of Medicine, University of Ljubljana , Vrazov trg 2, 1000 Ljubljana, Slovenia.
  • 3. Faculty of Pharmacy, Jagiellonian University , Medyczna 9 St., 30-688 Krakow, Poland.
  • 4. Institut de Recherche Biomédicale des Armées , 91223 Brétigny sur Orge, France.
  • 5. Institute of Biochemistry, Faculty of Medicine, University of Ljubljana , Vrazov trg 2, 1000 Ljubljana, Slovenia.
  • 6. University Grenoble Alpes, and CNRS and CEA, IBS , F-38044 Grenoble, France.
PMID: 29227101 DOI: 10.1021/acs.jmedchem.7b01086
Abstract

The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.

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