Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
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DOI：
10.1021/jm301020q
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发表时间：
2012-11-22
影响因子：
7.3
通讯作者：
Sweeney, Zachary K.
中科院分区：
文献类型：
--
作者：
Estrada, Anthony A.;Liu, Xingrong;Sweeney, Zachary K.
目前对强效、选择性和脑渗透的富含亮氨酸重复激酶2 （LRRK2）小分子抑制剂的需求很高，以测试是否抑制LRRK2激酶活性。是帕金森病患者潜在可行的治疗选择。在此，我们公开了利用基于性质和结构的药物设计来优化高配体效率的氨基嘧啶先导化合物。高通量体内啮齿动物药代动力学研究能够快速验证体内外相关性。在此基础上，确定了最优设计参数。有效。将这些指导原则结合到我们的分子设计过程中，我们发现了小分子抑制剂，如GNE-7915（18）和19，它们在LRRK2细胞效价、广泛的激酶选择性、代谢稳定性和跨多种物种的脑穿透性方面具有理想的平衡。GNE-7915在啮齿动物和高等物种毒性研究中的进展使早期发育的风险评估成为可能。
There is, a high-demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity. is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective. incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance Of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.