Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 17, Pages 5625-5629Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.06.104
Keywords
LRRK2; Drug discovery; Kinase inhibitors; Parkinson's disease
Categories
Funding
- Michael J. Fox Foundation for Parkinson's Research
- NIH [P41 GM079575-03]
- Medical Research Council
- Michael J Fox Foundation for Parkinson's Research
- DSTT (AstraZeneca)
- DSTT (Boehringer-Ingelheim)
- DSTT (GlaxoSmithKline)
- DSTT (Merck KgaA)
- DSTT (Pfizer)
- Medical Research Council [MC_U127070193, MC_G1000735, G0700656] Funding Source: researchfish
- MRC [MC_G1000735, G0700656, MC_U127070193] Funding Source: UKRI
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Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 mu M in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100 mg/kg. (C) 2012 Elsevier Ltd. All rights reserved.
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