Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

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• 作者：Anthony A. Estrada ; Xingrong Liu ; Charles Baker-Glenn ; Alan Beresford ; Daniel J. Burdick ; Mark Chambers ; Bryan K. Chan ; Huifen Chen ; Xiao Ding ; Antonio G. DiPasquale ; Sara L. Dominguez ; Jennafer Dotson ; Jason Drummond ; Michael Flagella ; Sean Flynn ; Reina Fuji ; Andrew Gill ; Janet Gunzner-Toste ; Seth F. Harris ; Timothy P. Heffron ; Tracy Kleinheinz ; Donna W. Lee ; Claire E. Le Pichon ; Joseph P. Lyssikatos ; Andrew D. Medhurst ; John G. Moffat ; Susmith Mukund ; Kevin Nash ; Kimberly Scearce-Levie ; Zejuan Sheng ; Daniel G. Shore ; Thuy Tran ; Naimisha Trivedi ; Shumei Wang ; Shuo Zhang ; Xiaolin Zhang ; Guiling Zhao ; Haitao Zhu ; Zachary K. Sweeney
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9416-9433
• 全文大小：673K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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鈥檚 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鈥搃n 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.