Journal of medicinal chemistry, 2015-01, Vol.58 (1), p.443-456
2015
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Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Journal of medicinal chemistry, 2015-01, Vol.58 (1), p.443-456
- Ort / Verlag
- United States: American Chemical Society
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2623eISSN: 1520-4804DOI: 10.1021/jm501557aTitel-ID: cdi_proquest_miscellaneous_1645774317
- Format
- –
- Schlagworte
- 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