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

Research output: Contribution to journal › Article › peer-review

140 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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@article{82b1d2d5b8ea46cb91f9519ec91b38fb,

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.\}",

year = "2012",

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

language = "English",

volume = "22",

pages = "5625--5629",

journal = "Bioorganic \& Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier",

number = "17",

}

TY - JOUR

T1 - GSK2578215A

T2 - a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

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

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/84865149238

U2 - 10.1016/j.bmcl.2012.06.104

DO - 10.1016/j.bmcl.2012.06.104

M3 - Article

C2 - 22863203

SN - 0960-894X

VL - 22

SP - 5625

EP - 5629

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 17

ER -

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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Projects

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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