Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 1, Pages 443-456Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501557a
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Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38 alpha 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 p38 alpha 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/p38 alpha MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38 alpha, 30 nM) and 14d (IC50: JNK3, 26 nM; p38 alpha, 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 Huntingtons disease.
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