Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), A Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor
Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), A Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor
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DOI：
10.1021/jm5014055
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发表时间：
2015-01-08
影响因子：
7.3
通讯作者：
Galatsis, Paul
中科院分区：
文献类型：
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作者：
Henderson, Jaclyn L.;Kormos, Bethany L.;Galatsis, Paul
全基因组关联研究（GWAS）发现富含亮氨酸重复序列激酶2（LRRK 2）与帕金森病（PD）存在遗传关联。最常见的LRRK 2突变G2019 S在总人群中相对罕见，导致激酶活性增加。因此，LRRK 2激酶抑制剂在治疗PD中是潜在有用的。我们在此公开了一系列新的有效的LRRK 2抑制剂的发现和优化，集中于使用替代晶体学方法改善激酶组选择性。这导致鉴定出14（PF-06447475），这是一种高效的脑渗透剂和选择性LRRK 2抑制剂，已在体内安全性和药效学研究中对其进行了进一步分析。
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinsons disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.