Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

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• 作者：Snahel Patel ; Seth F. Harris ; Paul Gibbons ; Gauri Deshmukh ; Amy Gustafson ; Terry Kellar ; Han Lin ; Xingrong Liu ; Yanzhou Liu ; Yichin Liu ; Changyou Ma ; Kimberly Scearce-Levie ; Arundhati Sengupta Ghosh ; Young G. Shin ; Hilda Solanoy ; Jian Wang ; Bei Wang ; Jianping Yin ; Michael Siu ; Joseph W. Lewcock
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8182-8199
• 全文大小：873K
• ISSN：1520-4804

文摘

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.