Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
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DOI：
10.1021/acs.jmedchem.7b00045
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发表时间：
2017-04-13
影响因子：
7.3
通讯作者：
Miller, Michael W.
中科院分区：
文献类型：
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作者：
Scott, Jack D.;DeMong, Duane E.;Miller, Michael W.
富含亮氨酸的重复序列激酶2（Leucine-rich repeat kinase 2，LRRK 2）是一种大的多结构域蛋白，其包含激酶结构域和GT3结构域。在激酶结构域中具有功能获得突变的个体，例如最普遍的G2019 S突变，与帕金森病（PD）发展的风险增加相关。鉴于这种抑制LRRK 2激酶活性作为影响疾病进展的潜在手段的遗传验证，我们的团队着手开发LRRK 2抑制剂来测试这一假设。我们的化合物收集的高通量筛选提供了一些有前途的吲唑的线索，其被截断，以确定一个最小的药效团。这些吲唑的进一步优化导致了MLi-2（1）的开发：一种有效的，高选择性的，口服的，脑渗透的LRRK 2抑制剂。
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.