Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease,Journal of Medicinal Chemistry

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Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00843
Snahel Patel , William J. Meilandt , Rebecca I. Erickson , Jinhua Chen ₁ , Gauri Deshmukh , Anthony A. Estrada , Reina N. Fuji , Paul Gibbons , Amy Gustafson , Seth F. Harris , Jose Imperio , Wendy Liu , Xingrong Liu , Yichin Liu , Joseph P. Lyssikatos , Changyou Ma ₁ , Jianping Yin , Joseph W. Lewcock , Michael Siu

Affiliation

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.

中文翻译：

双亮氨酸拉链激酶（DLK，MAP3K12）在阿尔茨海默氏病模型中的活性的选择性抑制剂。

存在大量数据表明双亮氨酸拉链激酶（DLK，MAP3K12）是神经元损伤后和慢性神经退行性疾病中神经元变性的保守调节剂。因此，人们对鉴定具有与这些适应症的发展相适应的特征的DLK抑制剂具有相当大的兴趣。在本文中，我们使用基于结构的药物设计与对CNS药物样性质的关注相结合，以产生与先前公开的DLK抑制剂相比具有优异的激酶选择性和代谢稳定性的化合物。这些化合物以抑制剂14为例，在给药超过数天后，在浓度超过脑中抑制DLK所需的浓度后，仍具有出色的CNS渗透性和良好的耐受性。

更新日期：2017-09-20

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