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Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) - Part 1.
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-12-01 , DOI: 10.1016/j.bmcl.2018.11.058
Joanne Osborne 1 , Kristian Birchall 1 , Denise J Tsagris 1 , Stephen J Lewis 1 , Ela Smiljanic-Hurley 1 , Debra L Taylor 1 , Alison Levy 1 , Dario R Alessi 2 , Edward G McIver 1
Affiliation  

Parkinson's disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further development.

中文翻译:

富含亮氨酸的重复激酶2(LRRK2)的有效和选择性5-氮杂吲唑抑制剂的发现-第1部分。

帕金森氏病是一种相对常见的神经系统疾病,发病率随着年龄的增长而增加。当前的治疗仅减轻症状并且不改变疾病的进程,因此鉴定疾病修饰疗法代表了显着的未满足的医学需求。LRRK2基因中的突变是PD发生的危险因素,并且据推测某些LRRK2突变体的激酶活性增强是造成多巴胺能神经元损伤的原因,因此LRRK2抑制剂提供了靶向该疾病潜在病因的潜力。 。在此交流中,我们描述了一系列新颖的5-氮杂吲唑类药物的铅化学药物程序。通过高通量筛选获得的化合物1被优化为具有前途DMPK特性的高效,选择性系列分子。发现在3-位引入杂环显着增加了效力和激酶选择性,而对4-氯苄基的改变改善了理化性质。我们的系列被许可给一家大型制药公司进行进一步开发。
更新日期:2018-12-01
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