Pyridinylimidazoles as dual glycogen synthase kinase 3β/p38α mitogen-activated protein kinase inhibitors.

Amino Acid Sequence Carbon-13 Magnetic Resonance Spectroscopy Glycogen Synthase Kinase 3 beta / antagonists & inhibitors Humans Imidazoles / chemistry Inhibitory Concentration 50 Molecular Docking Simulation Protein Kinase Inhibitors / pharmacology Proton Magnetic Resonance Spectroscopy Pyridines / chemistry Sequence Homology, Amino Acid Spectrometry, Mass, Electrospray Ionization Structure-Activity Relationship p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Alzheimer's disease Dual inhibitors Glycogen synthase kinase 3β Kinase inhibitors Pyridinylimidazoles p38α MAP kinase

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
01 Aug 2019
Historique:
received: 27 01 2019
revised: 29 03 2019
accepted: 13 04 2019
pubmed: 17 5 2019
medline: 16 7 2019
entrez: 17 5 2019
Statut: ppublish

Résumé

Compounds simultaneously inhibiting two targets that are involved in the progression of the same complex disease may exhibit additive or even synergistic therapeutic effects. Here we unveil 2,4,5-trisubstituted imidazoles as dual inhibitors of p38α mitogen-activated protein kinase and glycogen synthase kinase 3β (GSK3β). Both enzymes are potential therapeutic targets for neurodegenerative disorders, like Alzheimer's disease. A set of 39 compounds was synthesized and evaluated in kinase activity assays for their ability to inhibit both target kinases. Among the synthesized compounds, potent dual-target-directed inhibitors showing IC

Identifiants

DOI: 10.1016/j.ejmech.2019.04.035 PMID: 31096153
pubmed: 31096153
pii: S0223-5234(19)30350-2
doi: 10.1016/j.ejmech.2019.04.035
pii:
doi:

Substances chimiques

Imidazoles 0
Protein Kinase Inhibitors 0
Pyridines 0
GSK3B protein, human EC 2.7.11.1
Glycogen Synthase Kinase 3 beta EC 2.7.11.1
p38 Mitogen-Activated Protein Kinases EC 2.7.11.24
pyridine NH9L3PP67S

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

309-329

Informations de copyright

Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Auteurs

Fabian Heider (F)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Francesco Ansideri (F)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Roberta Tesch (R)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Tatu Pantsar (T)

School of Pharmacy, University of Eastern Finland, P.O. BOX 1627, 70211, Kuopio, Finland; Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Strasse 14, 72076, Tübingen, Germany.

Urs Haun (U)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Eva Döring (E)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Mark Kudolo (M)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Antti Poso (A)

School of Pharmacy, University of Eastern Finland, P.O. BOX 1627, 70211, Kuopio, Finland; Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Strasse 14, 72076, Tübingen, Germany.

Wolfgang Albrecht (W)

Teva-ratiopharm, Graf-Arco-Str. 3, 89079, Ulm, Germany.

Stefan A Laufer (SA)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

Pierre Koch (P)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany; Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany. Electronic address: pierre.koch@uni-tuebingen.de.

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Classifications MeSH

questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence d'acides aminés › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Analyse spectrale › Spectroscopie par résonance magnétique › Spectroscopie par résonance magnétique du carbone-13 › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Glycogen Synthase Kinase 3 › Glycogen synthase kinase 3 beta › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Concentration inhibitrice 50 › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Analyse spectrale › Spectroscopie par résonance magnétique › Spectroscopie par résonance magnétique du proton › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Phénomènes génétiques › Similitude de séquences › Similitude de séquences d'acides aminés › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Spectrométrie de masse › Spectrométrie de masse ESI › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Pyridinylimidazoles as dual glycogen synthase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Mitogen-Activated Protein Kinases › p38 Mitogen-Activated Protein Kinases › Pyridinylimidazoles as dual glycogen synthase...