GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

Alastair D. Reith; Paul Bamborough; Karamjit Jandu; Daniele Andreotti; Lucy Mensah; Pamela Dossang; Hwan Geun Choi; Xianming Deng; Jinwei Zhang; Dario R. Alessi; Nathanael S. Gray

doi:10.1016/j.bmcl.2012.06.104

GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

Alastair D. Reith, Paul Bamborough, Karamjit Jandu, Daniele Andreotti, Lucy Mensah, Pamela Dossang, Hwan Geun Choi, Xianming Deng, Jinwei Zhang, Dario R. Alessi, Nathanael S. Gray

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121 Citations (Scopus)

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

Original language	English
Pages (from-to)	5625-5629
Number of pages	5
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	22
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2012.06.104
Publication status	Published - 2012

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10.1016/j.bmcl.2012.06.104

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title = "GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor",

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

author = "Reith, {Alastair D.} and Paul Bamborough and Karamjit Jandu and Daniele Andreotti and Lucy Mensah and Pamela Dossang and Choi, {Hwan Geun} and Xianming Deng and Jinwei Zhang and Alessi, {Dario R.} and Gray, {Nathanael S.}",

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doi = "10.1016/j.bmcl.2012.06.104",

language = "English",

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AU - Reith, Alastair D.

AU - Bamborough, Paul

AU - Jandu, Karamjit

AU - Andreotti, Daniele

AU - Mensah, Lucy

AU - Dossang, Pamela

AU - Choi, Hwan Geun

AU - Deng, Xianming

AU - Zhang, Jinwei

AU - Alessi, Dario R.

AU - Gray, Nathanael S.

PY - 2012

Y1 - 2012

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

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DO - 10.1016/j.bmcl.2012.06.104

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GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

Abstract

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A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

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GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

Abstract

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A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

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