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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, 00:00 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.