Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease

Kai Guo; Roger Mutter; William Heal; Tummala R.K. Reddy; Hannah Cope; Steven Pratt; Mark J. Thompson; Beining Chen

doi:10.1016/j.ejmech.2007.02.018

Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease

Kai Guo, Roger Mutter, William Heal, Tummala R.K. Reddy, Hannah Cope, Steven Pratt, Mark J. Thompson, Beining Chen

University of Sheffield

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摘要

We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrP^C) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrP^Sc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrP^C whilst 12 showed discernable inhibition of PrP^Sc formation, five displaying EC₅₀s in the range 2.5-9 μM. Two compounds were found to reduce PrP^Sc levels to below 30% relative to an untreated control at 50 nM.

源语言	英语
页（从-至）	93-106
页数	14
期刊	European Journal of Medicinal Chemistry
卷	43
期	1
DOI	https://doi.org/10.1016/j.ejmech.2007.02.018
出版状态	已出版 - 1月 2008
已对外发布	是

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title = "Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease",

abstract = "We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrPC) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrPSc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrPC whilst 12 showed discernable inhibition of PrPSc formation, five displaying EC50s in the range 2.5-9 μM. Two compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50 nM.",

keywords = "Microwave irradiation, Prion protein, Pyridine dicarbonitriles, SPR, TSE, vCJD",

author = "Kai Guo and Roger Mutter and William Heal and Reddy, {Tummala R.K.} and Hannah Cope and Steven Pratt and Thompson, {Mark J.} and Beining Chen",

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AU - Guo, Kai

AU - Mutter, Roger

AU - Heal, William

AU - Reddy, Tummala R.K.

AU - Cope, Hannah

AU - Pratt, Steven

AU - Thompson, Mark J.

AU - Chen, Beining

PY - 2008/1

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AB - We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrPC) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrPSc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrPC whilst 12 showed discernable inhibition of PrPSc formation, five displaying EC50s in the range 2.5-9 μM. Two compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50 nM.

KW - Microwave irradiation

KW - Prion protein

KW - Pyridine dicarbonitriles

KW - SPR

KW - TSE

KW - vCJD

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Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease

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