The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson’s disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood–brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure–activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor’s brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics.

中文翻译：

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新型大环 LRRK2 抑制剂的功效和血脑屏障渗透性的同时优化，用于潜在的帕金森病治疗

富含亮氨酸重复激酶 2 (LRRK2) 活性升高与帕金森病 (PD) 的发病机制有关。跨越血脑屏障 (BBB) 的艰巨挑战阻碍了对有效 LRRK2 抑制剂的探索。我们利用基于结构的从头设计，开发了稳健的三维定量结构-活性关系 (3D-QSAR) 模型来预测 BBB 通透性，从而提高抑制剂进入大脑的可能性。我们的策略涉及通过将 HG-10-102-01 的两个末端氮原子与 2 至 4 个单元的烷基链连接来合成大环分子，为创新的 LRRK2 抑制剂设计奠定基础。通过对生化功效和血脑屏障渗透性进行细致的计算和合成优化，14 种合成候选物中的 9 种表现出有效的低纳摩尔抑制和显着的血脑屏障渗透性。对体外和体内有效性的进一步评估以及药理学分析表明8是有前途的 PD 治疗新先导化合物。