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

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

81 Scopus citations

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 (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.

Original language	English
Pages (from-to)	93-106
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	43
Issue number	1
DOIs	https://doi.org/10.1016/j.ejmech.2007.02.018
State	Published - Jan 2008
Externally published	Yes

Keywords

Microwave irradiation
Prion protein
Pyridine dicarbonitriles
SPR
TSE
vCJD

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2007.02.018

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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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JO - European Journal of Medicinal Chemistry

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

Abstract

Keywords

UN SDGs

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