期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 19, 页码 8083-8102出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00843
关键词
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资金
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-ACO2- 05CH11231]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Center for Research Resources [P41RR001209]
Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.
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