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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

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journal contribution
posted on 08.01.2015 by 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
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.