Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases

Felix Muth; Marcel Günther; Silke M Bauer; Eva Döring; Sabine Fischer; Julia Maier; Peter Drückes; Jürgen Köppler; Jörg Trappe; Ulrich Rothbauer; Pierre Koch; Stefan A Laufer

doi:10.1021/jm501557a

Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases

J Med Chem. 2015 Jan 8;58(1):443-56. doi: 10.1021/jm501557a. Epub 2014 Dec 5.

Authors

Felix Muth¹, Marcel Günther, Silke M Bauer, Eva Döring, Sabine Fischer, Julia Maier, Peter Drückes, Jürgen Köppler, Jörg Trappe, Ulrich Rothbauer, Pierre Koch, Stefan A Laufer

Affiliation

¹ Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.

PMID: 25475894
DOI: 10.1021/jm501557a

Abstract

Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38α, 30 nM) and 14d (IC50: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington's disease.

MeSH terms

Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design
Humans
Huntington Disease / drug therapy
Imidazoles / chemistry
Imidazoles / metabolism
Imidazoles / pharmacology*
Male
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 10 / chemistry
Mitogen-Activated Protein Kinase 10 / metabolism
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / chemistry
Mitogen-Activated Protein Kinase 14 / metabolism
Models, Chemical
Models, Molecular
Molecular Structure
Neurodegenerative Diseases / drug therapy*
Protein Binding
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Structure, Tertiary
Pyridines / chemistry
Pyridines / metabolism
Pyridines / pharmacology*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology

Substances

Imidazoles
Protein Kinase Inhibitors
Pyridines
Small Molecule Libraries
Mitogen-Activated Protein Kinase 10
Mitogen-Activated Protein Kinase 14