GSK2578215A；一种有效的、高度选择性的 2-芳基甲氧基-5-取代-N-芳基苯甲酰胺 LRRK2 激酶抑制剂。
GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor.
机构信息
External Alliances & Development, R&D China, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK.
出版信息
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9. doi: 10.1016/j.bmcl.2012.06.104. Epub 2012 Jul 7.
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.
摘要
富含亮氨酸重复激酶 2（LRRK2）是某些帕金森病形式的有前途的治疗靶标。在这里，我们报告了具有强效 LRRK2 活性的 2-芳基甲氧基-5-取代-N-芳基苯甲酰胺的发现和表征，其中 GSK2578215A 是一个很好的例子，其对野生型 LRRK2 和 G2019S 突变体的生化 IC50 约为 10 nM。GSK2578215A 在激酶组中对 LRRK2 具有极高的选择性，在腹腔注射 100mg/kg 后，在细胞和小鼠脾脏和肾脏中，浓度为 0.3-1.0 μM 时，可显著抑制野生型 LRRK2 和 G2019S 突变体的 Ser910 和 Ser935 磷酸化，但在大脑中没有。
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