Publications | GSK2578215A A potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

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 10nM 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 0.3-1.0muM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.

Principal Investigator(s):

Author(s):
Reith, A. D., Bamborough, P., Jandu, K., Andreotti, D., Mensah, L., Dossang, P., Choi, H. G., Deng, X., Zhang, J., Alessi, D. R., Gray, N. S.

PubMed:
22863203
Citation:
Reith, A. D., Bamborough, P., Jandu, K., Andreotti, D., Mensah, L., Dossang, P., Choi, H. G., Deng, X., Zhang, J., Alessi, D. R., Gray, N. S.
Bioorg Med Chem Lett
2012
22
5625-5629
PMID: 22863203