Publications by authors named "Stefanie Hagenow"

17 Publications

  • Page 1 of 1

Adenosine AR/AR Antagonists Enabling Additional HR Antagonism for the Treatment of Parkinson's Disease.

J Med Chem 2021 Jun 9;64(12):8246-8262. Epub 2021 Jun 9.

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.

Adenosine A/A receptors (AR/AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H receptor (HR) antagonists in combination with the "caffeine-like effects" of AR/AR antagonists, we designed AR/AR/HR MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl HR pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar HR affinities ( < 55 nM). Compound (, (AR) = 11.5 nM, (AR) = 7.25 nM) and (, (AR) = 11.2 nM, (AR) = 4.01 nM) were evaluated . l-DOPA-induced dyskinesia was improved after administration of compound (1 mg kg, i.p. rats). Compound (2 mg kg, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00914DOI Listing
June 2021

Parameters for Irreversible Inactivation of Monoamine Oxidase.

Molecules 2020 Dec 13;25(24). Epub 2020 Dec 13.

Department of Health and Drug Sciences, University of Catania, Viale A. Doria 6 ed. 2, I-95125 Catania, Italy.

The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The K values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH influences the formation of the covalent adduct essential for effective inactivation of MAO.
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http://dx.doi.org/10.3390/molecules25245908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763263PMC
December 2020

Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ aggregation.

Bioorg Chem 2020 05 4;98:103722. Epub 2020 Mar 4.

Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Química, Grupo de Investigación en Productos Naturales Vegetales Bioactivos, Cr 30 N°45-03, 111321 Bogotá, Colombia.

Multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatments [6]. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new anti-AD drug candidates. Herein described natural isoquinoline alkaloids were investigated for multi-target activity on key mechanisms associated with the AD's pathogenesis, i.e. cholinergic depletion, beta amyloid (Aβ) aggregation and oxidative stress. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aβ aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (5) and avicine (7), as the most potent multi-target candidates. Both showed dual cholinesterase inhibition, being more active against AChE over BChE, with IC values in sub-micromolar range in AChE. Kinetic analysis with cholinesterase showed, that both compounds are reversible-mixed inhibitors, where avicine (7) presented highest potency with K values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). In addition, these alkaloids presented moderate Aβ anti-aggregation activity and MAO-A inhibition with IC values between 0.5 and 2 µM. Our findings suggest that avicine (7) is a promising natural compound and multifunctional candidate representing a suitable starting point for the development of new therapeutic agents for Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2020.103722DOI Listing
May 2020

Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs.

Drug Des Devel Ther 2020 28;14:371-393. Epub 2020 Jan 28.

Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Duesseldorf 40225, Germany.

Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors.

Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results.

Results: -(2,4-Dinitrophenyl)benzo[][1,3]dioxole-5-carboxamide (, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC = 56 nM, K = 6.3 nM), while -(2,4-dinitrophenyl)benzamide (, ST-2023) showed higher preference for MAO A (IC = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites.

Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.
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http://dx.doi.org/10.2147/DDDT.S236586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996489PMC
January 2021

Search for new multi-target compounds against Alzheimer's disease among histamine H receptor ligands.

Eur J Med Chem 2020 Jan 17;185:111785. Epub 2019 Oct 17.

Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against HR and both enzymes. Two derivatives were chosen - 5 (IC = 0.46 μM (AChE); 0.44 μM (BuChE); K = 159.8 nM (HR)) and 17 (IC = 0.50 μM (AChE); 0.76 μM (BuChE); K = 228.2 nM (HR)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.
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http://dx.doi.org/10.1016/j.ejmech.2019.111785DOI Listing
January 2020

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H receptor ligands.

Bioorg Chem 2019 10 20;91:103071. Epub 2019 Jun 20.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H receptor (hHR) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hHR affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hHR K = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at HR, as well as drug-like properties of selected ligands were evaluated using in vitro methods.
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http://dx.doi.org/10.1016/j.bioorg.2019.103071DOI Listing
October 2019

Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands.

PLoS One 2019 25;14(6):e0218820. Epub 2019 Jun 25.

Molecular Design Lab, Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.

In this study, we report a ligand-guided homology modeling approach allowing the analysis of relevant binding site residue conformations and the identification of two novel histamine H3 receptor ligands with binding affinity in the nanomolar range. The newly developed method is based on exploiting an essential charge interaction characteristic for aminergic G-protein coupled receptors for ranking 3D receptor models appropriate for the discovery of novel compounds through virtual screening.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592549PMC
February 2020

Alkyl derivatives of 1,3,5-triazine as histamine H receptor ligands.

Bioorg Med Chem 2019 04 12;27(7):1254-1262. Epub 2019 Feb 12.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland.

This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H receptor (hHR) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hHR affinity with a K of 160 nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC = 32 nM) and [S]GTPγS binding assay (pK = 6.67). In addition, antinociceptive activity of 14in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats).
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http://dx.doi.org/10.1016/j.bmc.2019.02.020DOI Listing
April 2019

Optimization and preclinical evaluation of novel histamine Hreceptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives.

Bioorg Med Chem 2018 12 10;26(23-24):6056-6066. Epub 2018 Nov 10.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

As a continuation of our search for novel histamine H receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H receptors (hHR). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hHR affinity (hHR K = 5.2-115 nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hHR K = 5.2 and 15.4 nM vs. 10.2 and 115 nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.
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http://dx.doi.org/10.1016/j.bmc.2018.11.010DOI Listing
December 2018

Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and Studies.

Front Chem 2018 3;6:247. Epub 2018 Jul 3.

Department of Chemistry and Biochemistry, Faculty of Agriculture, University of Belgrade, Belgrade, Serbia.

The novel approach in the treatment of complex multifactorial diseases, such as neurodegenerative disorders and cancer, requires a development of efficient multi-targeting oriented drugs. Since oxidative stress significantly contributes to the pathogenesis of cancer and neurodegenerative disorders, potential drug candidates should possess good antioxidant properties. Due to promising biological activities shown for structurally related (1,3-thiazol-2-yl)hydrazones, a focused library of 12 structurally related benzylidene-based (1,3-selenazol-2-yl)hydrazones was designed as potential multi-targeting compounds. Monoamine oxidases (MAO) A/B inhibition properties of this class of compounds have been investigated. Surprisingly, the -nitrophenyl-substituted (1,3-selenazol-2-yl)hydrazone showed MAO B inhibition in a nanomolar concentration range (IC = 73 nM). Excellent antioxidant properties were confirmed in a number of different assays. Antiproliferative activity screening on a panel of six human solid tumor cell lines showed that potencies of some of the investigated compounds was comparable or even better than that of the positive control 5-fluorouracil. calculations of ADME properties pointed to promising good pharmacokinetic profiles of investigated compounds. Docking studies suggest that some compounds, compared to positive controls, have the ability to strongly interact with targets relevant to cancer such as 5'-nucleotidase, and to neurodegenerative diseases such as the small conductance calcium-activated potassium channel protein 1, in addition to confirmation of inhibitory binding at MAO B.
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http://dx.doi.org/10.3389/fchem.2018.00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037691PMC
July 2018

Design, synthesis, and biological evaluation of novel oxadiazole- and thiazole-based histamine HR ligands.

Bioorg Med Chem 2018 08 21;26(14):4034-4046. Epub 2018 Jun 21.

Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany. Electronic address:

Histamine H receptor (HR) is largely expressed in the CNS and modulation of the HR function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting HR with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based HR ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range. Ligands combining 4-cyanophenyl moiety as arbitrary region, para-xylene or piperidine carbamoyl linkers, and/or pyrrolidine or piperidine basic heads were found to be the most active within this series of thiazole-based HR ligands. The most active ligands were in silico screened for ADMET properties and drug-likeness. They fulfilled Lipinski's and Veber's rules and exhibited potential activities for oral administration, blood-brain barrier penetration, low hepatotoxicity, combined with an overall good toxicity profile.
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http://dx.doi.org/10.1016/j.bmc.2018.06.028DOI Listing
August 2018

Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine HR ligands.

Eur J Med Chem 2018 May 25;152:223-234. Epub 2018 Apr 25.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

As a continuation of our search for novel histamine H receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H receptor (hHR). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (K = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional HR antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in HR ligands.
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http://dx.doi.org/10.1016/j.ejmech.2018.04.043DOI Listing
May 2018

Novel naphthyloxy derivatives - Potent histamine H receptor ligands. Synthesis and pharmacological evaluation.

Bioorg Med Chem 2018 05 11;26(9):2573-2585. Epub 2018 Apr 11.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address:

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H receptor affinity. Most compounds showed high affinities with K values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H receptor with a K value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC = 312 nM) and in vivo in the rat dipsogenia model (ED = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED = 30.6 mg/kg (early phase) and ED = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; HR K = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED of 33.1 mg/kg and (44 mA) ED of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H receptor ligands with promising in vitro and in vivo activity.
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http://dx.doi.org/10.1016/j.bmc.2018.04.023DOI Listing
May 2018

Novel indanone derivatives as MAO B/HR dual-targeting ligands for treatment of Parkinson's disease.

Eur J Med Chem 2018 Mar 16;148:487-497. Epub 2018 Feb 16.

Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetstr. 1, 40225 Duesseldorf, Germany. Electronic address:

The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H receptor (HR) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the HR pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/HR DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hHR affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC values ranging from 1931 nM to 276 nM and high affinities at hHR (K < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC = 276 nM, hHR K = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC = 232 nM), a structural isomer of 3f, and 3d (MAO B IC = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hHR DTLs as novel therapeutic approach of PD therapy.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.015DOI Listing
March 2018

Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H R Antagonism for Neurodegenerative Diseases.

Angew Chem Int Ed Engl 2017 10 1;56(41):12765-12769. Epub 2017 Sep 1.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
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http://dx.doi.org/10.1002/anie.201706072DOI Listing
October 2017

Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands.

ACS Med Chem Lett 2017 Jun 4;8(6):648-653. Epub 2017 May 4.

Pharmaceutical and Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.

In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect. validation of the modeling results revealed that three known modulators of melanin-concentrating hormone receptor 1 (MCHR1) show a previously unknown submicromolar affinity to the histamine H3 receptor (HR). This synergistic activity may present a novel therapeutic option against obesity.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467185PMC
June 2017
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