Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer's disease
- Title
- Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer's disease
- Author
- 하정미
- Keywords
- JNK3; Imidazole; Neurodegenerative diseases; Alzheimer’s disease; APP/PS1; 3xTg; mouse
- Issue Date
- 2022-10-02
- Publisher
- ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
- Citation
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- Abstract
- Despite innumerable efforts to develop effective therapeutics, it is difficult to achieve breakthrough treatments for Alzheimer's disease (AD), and the main reason is probably the absence of a clear target. Here, we reveal c-Jun N-terminal kinase 3 (JNK3), a protein kinase explicitly expressed in the brain and involved in neuronal apoptosis, with a view toward providing effective treatment for AD. For many years, we have worked on JNK3 inhibitors and have discovered 2-aryl-1-pyrimidinyl-1H-imidazole-5-yl acetonitrile-based JNK3 inhibitors with superb potency (IC50 ˂ 1.0 nM) and excellent selectivity over other protein kinases including isoforms JNK1 (˃300 fold) and JNK2 (similar to 10 fold). Based on in vitro biological activity and DMPK properties, the lead compounds were selected for further in vivo studies. We confirmed that repeat administration of JNK3 inhibitors improved cognitive memory in APP/PS1 and the 3xTg mouse model. Overall, our results show that JNK3 could be a potential target protein for AD.
- URI
- https://www.sciencedirect.com/science/article/pii/S0223523422007966https://repository.hanyang.ac.kr/handle/20.500.11754/189608
- ISSN
- 0223-5234
- DOI
- https://doi.org/10.1016/j.ejmech.2022.114894
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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