Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2

被引：35

作者：

Troxler, Thomas ^{[1
]}

Greenidge, Paulette ^{[1
]}

Zimmermann, Kaspar ^{[1
]}

Desrayaud, Sandrine ^{[1
]}

Drueckes, Peter ^{[2
]}

Schweizer, Tatjana ^{[1
]}

Stauffer, Daniela ^{[1
]}

Rovelli, Giorgio ^{[1
]}

Shimshek, Derya R. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

[2] Novartis Inst BioMed Res, Ctr Prote Chem, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 14期

关键词：

Leucine-rich repeat kinase 2; LRRK2; inhibitors; Kinase inhibitors; Parkinson's disease; REPEAT KINASE 2; DISEASE-ASSOCIATED MUTATIONS; GENOME-WIDE ASSOCIATION; PARKINSONS-DISEASE; SUSCEPTIBILITY LOCI; G2019S MUTATION; CROHNS-DISEASE; PHOSPHORYLATION; MUTANT; SUBSTRATE;

D O I：

10.1016/j.bmcl.2013.05.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4085 / 4090

页数：6

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