Author/Editor | Košak, Urban; Brus, Boris; Knez, Damijan; Žakelj, Simon; Trontelj, Jurij; Pišlar, Anja; Šink, Roman; Jukič, Marko; Živin, Marko; Podkowa, Adrian; Nachon, Florian; Brazzolotto, Xavier; Stojan, Jure; Kos, Janko; Coquelle, Nicolas; Sałat, Kinga; Colletier, Jacques-Philippe; Gobec, Stanislav | |
Title | The magic of crystal structure-based Inhibitor optimization | |
Type | članek | |
Vol. and No. | Letnik 61, št. 1 | |
Publication year | 2018 | |
Volume | str. 119-139 | |
ISSN | 0022-2623 - Journal of medicinal chemistry | |
Language | eng | |
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-% interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo, and is non-cytotoxic. 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. | |
Descriptors | Alzheimerjeva bolezen |