三唑并吡啶 LRRK2 激酶抑制剂。
Triazolopyridazine LRRK2 kinase inhibitors.
机构信息
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA.
出版信息
Bioorg Med Chem Lett. 2013 Apr 1;23(7):1967-73. doi: 10.1016/j.bmcl.2013.02.043. Epub 2013 Feb 14.
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.
富含亮氨酸重复激酶 2（LRRK2）与帕金森病（PD）的发病机制有关。抑制 LRRK2 激酶活性是一种治疗方法，可能为 PD 带来新的治疗方法。本文报道了一系列[1,2,4]三唑并[4,3-b]哒嗪的发现，它们在生化测定中对野生型和突变型 LRRK2 激酶活性均具有很强的抑制作用，并且对 G2019S 突变体表现出前所未有的选择性。提出了观察到的选择性的结构合理性。
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