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