Brus B

References (10)

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 : N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents - Kosak_2017_Bioorg.Med.Chem_25_633
Author(s) : Kosak U , Knez D , Coquelle N , Brus B , Pislar A , Nachon F , Brazzolotto X , Kos J , Colletier JP , Gobec S
Ref : Bioorganic & Medicinal Chemistry , 25 :633 , 2017
Abstract : In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid beta-peptide species.
ESTHER : Kosak_2017_Bioorg.Med.Chem_25_633
PubMedSearch : Kosak_2017_Bioorg.Med.Chem_25_633
PubMedID: 27908752
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 : Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and beta-amyloid aggregation inhibitors with neuroprotective properties - Guzior_2015_Eur.J.Med.Chem_92C_738
Author(s) : Guzior N , Bajda M , Skrok M , Kurpiewska K , Lewinski K , Brus B , Pislar A , Kos J , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 92C :738 , 2015
Abstract : The presented study describes the synthesis, pharmacological evaluation (AChE and BCHE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 muM). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 muM) possesses additional properties, such as the ability to inhibit Abeta aggregation (65.96% at 10 muM) and a neuroprotective effect against Abeta toxicity at 1 and 3 muM. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders.
ESTHER : Guzior_2015_Eur.J.Med.Chem_92C_738
PubMedSearch : Guzior_2015_Eur.J.Med.Chem_92C_738
PubMedID: 25621991

Title : LiSiCA: A Software for Ligand-Based Virtual Screening and Its Application for the Discovery of Butyrylcholinesterase Inhibitors - Lesnik_2015_J.Chem.Inf.Model_55_1521
Author(s) : Lesnik S , Stular T , Brus B , Knez D , Gobec S , Janezic D , Konc J
Ref : J Chem Inf Model , 55 :1521 , 2015
Abstract : We developed LiSiCA (ligand similarity using clique algorithm)-ligand-based virtual screening software that uses a fast maximum clique algorithm to find two- and three-dimensional similarities between pairs of molecules and applied it to the discovery of novel potent butyrylcholinesterase inhibitors. LiSiCA, which runs in parallel on multiple processor cores, was successfully tested on the Database of Useful Decoys-Enhanced, to evaluate its ability to discriminate active molecules from decoys. We then applied LiSiCA for the discovery of novel inhibitors of human butyrylcholinesterase, a promising anti-Alzheimer target, using a known inhibitor as the reference compound. We demonstrated that LiSiCA is capable of finding potent nanomolar inhibitors, whose scaffolds differed from the reference compound, thus proving its ability for scaffold hopping and usefulness in drug discovery.
ESTHER : Lesnik_2015_J.Chem.Inf.Model_55_1521
PubMedSearch : Lesnik_2015_J.Chem.Inf.Model_55_1521
PubMedID: 26158767

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

Title : Multiple Ligands Targeting Cholinesterases and beta-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore - Szalaj_2015_Arch.Pharm.(Weinheim)_348_556
Author(s) : Szalaj N , Bajda M , Dudek K , Brus B , Gobec S , Malawska B
Ref : Arch Pharm (Weinheim) , 348 :556 , 2015
Abstract : Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50 = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent.
ESTHER : Szalaj_2015_Arch.Pharm.(Weinheim)_348_556
PubMedSearch : Szalaj_2015_Arch.Pharm.(Weinheim)_348_556
PubMedID: 26032855

Title : Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer's agents - Guzior_2015_Bioorg.Med.Chem_23_1629
Author(s) : Guzior N , Bajda M , Rakoczy J , Brus B , Gobec S , Malawska B
Ref : Bioorganic & Medicinal Chemistry , 23 :1629 , 2015
Abstract : Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and beta-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N-benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50=0.361muM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents.
ESTHER : Guzior_2015_Bioorg.Med.Chem_23_1629
PubMedSearch : Guzior_2015_Bioorg.Med.Chem_23_1629
PubMedID: 25707322

Title : Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with beta-amyloid anti-aggregation properties and beneficial effects on memory in vivo - Wieckowska_2015_Bioorg.Med.Chem_23_2445
Author(s) : Wieckowska A , Wieckowski K , Bajda M , Brus B , Salat K , Czerwinska P , Gobec S , Filipek B , Malawska B
Ref : Bioorganic & Medicinal Chemistry , 23 :2445 , 2015
Abstract : Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and beta-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and beta-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of beta-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50=0.72muM) that has beta-amyloid anti-aggregation activity (72.5% inhibition at 10muM) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents.
ESTHER : Wieckowska_2015_Bioorg.Med.Chem_23_2445
PubMedSearch : Wieckowska_2015_Bioorg.Med.Chem_23_2445
PubMedID: 25868744

Title : Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor - Brus_2014_J.Med.Chem_57_8167
Author(s) : Brus B , Kosak U , Turk S , Pislar A , Coquelle N , Kos J , Stojan J , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 57 :8167 , 2014
Abstract : Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid beta1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 muM) and protected cultured SH-SY5Y cells against amyloid-beta-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.
ESTHER : Brus_2014_J.Med.Chem_57_8167
PubMedSearch : Brus_2014_J.Med.Chem_57_8167
PubMedID: 25226236
Gene_locus related to this paper: human-BCHE