Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s 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.

中文翻译：

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高活性，选择性强的脑渗透剂3- [4-（吗啉-4-基）-7 H-吡咯并[2,3 - d ]嘧啶-5-基]苄腈（PF-06447475）的发现和临床前分析和体内活性LRRK2激酶抑制剂

富含亮氨酸的重复激酶2（LRRK2）已通过全基因组关联研究（GWAS）与帕金森氏病（PD）遗传相关。最常见的LRRK2突变G2019S在总人群中相对较少，导致激酶活性增加。这样，LRRK2激酶抑制剂可潜在地用于治疗PD。我们在此公开了一系列新颖的有效LRRK2抑制剂的发现和优化，其重点在于使用替代晶体学方法改善kinome的选择性。这导致鉴定出14（PF-06447475），这是一种高效的，脑渗透性和选择性LRRK2抑制剂，已在体内安全性和药效学研究中进行了进一步概述。