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

Troxler, Thomas J. and Greenidge, Paulette and Zimmermann, Kaspar and Desrayaud, Sandrine and Drueckes, Peter and Schweizer, Tatjana and Stauffer, Daniela and Rovelli, Giorgio and Shimshek, Derya (2013) Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2. Bioorganic & Medicinal Chemistry Letters, 23 (14). pp. 4085-4090. ISSN 0960894X

Abstract

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.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 04 Jul 2016 23:46
URI: https://oak.novartis.com/id/eprint/9882

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