학술논문
Discovery of Highly Potent,Selective, and Brain-PenetrantAminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small MoleculeInhibitors.
Document Type
Article
Author
Estrada, Anthony A.; Chan, Bryan K.; Baker-Glenn, Charles; Beresford, Alan; Burdick, Daniel J.; Chambers, Mark; Chen, Huifen; Dominguez, Sara L.; Dotson, Jennafer; Drummond, Jason; Flagella, Michael; Fuji, Reina; Gill, Andrew; Halladay, Jason; Harris, Seth F.; Heffron, Timothy P.; Kleinheinz, Tracy; Lee, Donna W.; Pichon, Claire E. Le; Liu, Xingrong
Source
Subject
*PYRAZOLES
*DARDARIN
*BRAIN physiology
*NEUROSCIENCES
*CHEMICAL stability
*LIVER cells
*LABORATORY rats
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Language
ISSN
0022-2623
Abstract
Leucine-rich repeat kinase 2 (LRRK2)has drawn significant interestin the neuroscience research community because it is one of the mostcompelling targets for a potential disease-modifying Parkinson’sdisease therapy. Herein, we disclose structurally diverse small moleculeinhibitors suitable for assessing the implications of sustained invivo LRRK2 inhibition. Using previously reported aminopyrazole 2as a lead molecule, we were able to engineer structuralmodifications in the solvent-exposed region of the ATP-binding sitethat significantly improve human hepatocyte stability, rat free brainexposure, and CYP inhibition and induction liabilities. Disciplinedapplication of established optimal CNS design parameters culminatedin the rapid identification of GNE-0877(11) and GNE-9605(20) as highly potent andselective LRRK2 inhibitors. The demonstrated metabolic stability,brain penetration across multiple species, and selectivity of theseinhibitors support their use in preclinical efficacy and safety studies. [ABSTRACT FROM AUTHOR]