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

doi:10.1016/j.bmcl.2012.06.104

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 17, 1 September 2012, Pages 5625-5629

https://doi.org/10.1016/j.bmcl.2012.06.104 Get rights and content

Abstract

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 IC₅₀s 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 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100 mg/kg.

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Acknowledgments

Mouse pharmacokinetic studies were performed at SAI Advantium (http://www.saiadvantium.com/) following their standard operating procedures which are subject to SAI’s policies on care, welfare and treatment of laboratory animals which were also reviewed and approved by the animal welfare committee of the Dana Farber Cancer Institute. All animal studies undertaken in the laboratory of Prof. Dario Alessi were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act

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^†: Present address: Biofocus, Chesterford Research Park, UK.

^‡: Present address: Aptuit (Verona), Italy.

^§: Present address: Vernalis (R&D) Ltd, Granta Park, Cambridge, UK.

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

Lancet Neurol.

Nat. Chem. Biol.

J. Neurosci. Res.

Neurology

Neuro-Signals

Arch. Neurol.

ASN Neuro

Expert Rev. Mol. Med.