Filipek B

References (3)

Title : Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives - Jonczyk_2019_Bioorg.Chem_90_103084
Author(s) : Jonczyk J , Lodarski K , Staszewski M , Godyn J , Zareba P , Soukup O , Janockova J , Korabecny J , Salat K , Malikowska-Racia N , Hebda M , Szalaj N , Filipek B , Walczynski K , Malawska B , Bajda M
Ref : Bioorg Chem , 90 :103084 , 2019
Abstract : In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2=8.27), inhibitory activity against both AChE (IC50=13.96muM), and BuChE (IC50=14.62muM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
ESTHER : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedSearch : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedID: 31271942

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 : 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