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

被引：103

作者：

Estrada, Anthony A. ^{[1
]}

Chan, Bryan K. ^{[1
]}

Baker-Glenn, Charles ^{[7
]}

Beresford, Alan ^{[9
]}

Burdick, Daniel J. ^{[1
]}

Chambers, Mark ^{[7
]}

Chen, Huifen ^{[1
]}

Dominguez, Sara L. ^{[2
]}

Dotson, Jennafer ^{[1
]}

Drummond, Jason ^{[3
]}

Flagella, Michael ^{[5
]}

Fuji, Reina ^{[5
]}

Gill, Andrew ^{[8
]}

Halladay, Jason ^{[4
]}

Harris, Seth F. ^{[6
]}

Heffron, Timothy P. ^{[1
]}

Kleinheinz, Tracy ^{[3
]}

Lee, Donna W. ^{[5
]}

Le Pichon, Claire E. ^{[2
]}

Liu, Xingrong ^{[4
]}

Lyssikatos, Joseph P. ^{[1
]}

Medhurst, Andrew D. ^{[8
]}

Moffat, John G. ^{[3
]}

Nash, Kevin ^{[8
]}

Scearce-Levie, Kimberly ^{[2
]}

Sheng, Zejuan ^{[2
]}

Shore, Daniel G. ^{[1
]}

Wong, Susan ^{[4
]}

Zhang, Shuo ^{[2
]}

Zhang, Xiaolin ^{[4
]}

Zhu, Haitao ^{[2
]}

Sweeney, Zachary K. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Safety Assessment, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[7] BioFocus, Dept Chem, Saffron Walden CB10 1XL, Essex, England

[8] BioFocus, Dept Biochem & Cellular Pharmacol, Saffron Walden CB10 1XL, Essex, England

[9] BioFocus, Dept Drug Metab & Pharmacokinet, Saffron Walden CB10 1XL, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 03期

关键词：

PARKINSONS-DISEASE; MOTOR FLUCTUATIONS; MUTATIONS; SURROGATE; ALIGNMENT; EXPOSURE; RAT;

D O I：

10.1021/jm401654j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 LARK2 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.

引用

页码：921 / 936

页数：16

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