Sink R

References (3)

Title : The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity - Kosak_2018_J.Med.Chem_61_119
Author(s) : Kosak U , Brus B , Knez D , Zakelj S , Trontelj J , Pislar A , Sink R , Jukic M , Zivin M , Podkowa A , Nachon F , Brazzolotto X , Stojan J , Kos J , Coquelle N , Salat K , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 61 :119 , 2018
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-pi 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.
ESTHER : Kosak_2018_J.Med.Chem_61_119
PubMedSearch : Kosak_2018_J.Med.Chem_61_119
PubMedID: 29227101
Gene_locus related to this paper: human-BCHE

Title : Development of an in-vivo active reversible butyrylcholinesterase inhibitor - Kosak_2016_Sci.Rep_6_39495
Author(s) : Kosak U , Brus B , Knez D , Sink R , Zakelj S , Trontelj J , Pislar A , Slenc J , Gobec M , Zivin M , Tratnjek L , Perse M , Salat K , Podkowa A , Filipek B , Nachon F , Brazzolotto X , Wieckowska A , Malawska B , Stojan J , Rascan IM , Kos J , Coquelle N , Colletier JP , Gobec S
Ref : Sci Rep , 6 :39495 , 2016
Abstract : Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.
ESTHER : Kosak_2016_Sci.Rep_6_39495
PubMedSearch : Kosak_2016_Sci.Rep_6_39495
PubMedID: 28000737
Gene_locus related to this paper: human-BCHE

Title : Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents - Knez_2015_Bioorg.Med.Chem_23_4442
Author(s) : Knez D , Brus B , Coquelle N , Sosic I , Sink R , Brazzolotto X , Mravljak J , Colletier JP , Gobec S
Ref : Bioorganic & Medicinal Chemistry , 23 :4442 , 2015
Abstract : Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Abeta1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215 nM), and also selectively complexes Cu(2+). Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
ESTHER : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedSearch : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedID: 26116179
Gene_locus related to this paper: human-BCHE