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

作者：Anthony A. Estrada, Bryan Chan, Charles Baker‐Glenn, Alan Beresford, Daniel J. Burdick, M.G. Chambers, Huifen Chen, Sara L. Domínguez, Jennafer Dotson, Jason Drummond, Michael Flagella, Reina N. Fuji, Andrew B. Gill, Jason Halladay, Seth F. Harris, Timothy P. Heffron, Tracy Kleinheinz, Donna W. Lee, Claire E. Le Pichon, Xingrong Liu, Joseph P. Lyssikatos, Andrew D. Medhurst, John G. Moffat, Kevin M. Nash, Kimberly Scearce‐Levie, Zejuan Sheng, Daniel G. Shore, Susan Wong, Shuo Zhang, Xiaolin Zhang, Haitao Zhu, Zachary K. Sweeney · 发表于：Journal of Medicinal Chemistry · 年份：2013 · DOI：10.1021/jm401654j · 被引用次数：126 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Cholinesterase and Neurodegenerative Diseases、Computational Drug Discovery Methods

Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.