Synthesis and Evaluation of a Focused Library of Pyridine Dicarbonitriles Against Prion Disease

Kai  Guo; Roger  Mutter; William  Heal; Tummala Rama Krishna 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 Rama Krishna Reddy
, Hannah Cope
, Steven Pratt
, Mark J. Thompson
, Beining Chen

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

80 Citations (Scopus)

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 2.5e9 mM. Two compounds were found to reduce PrPSc
levels to below 30% relative to an untreated control at 50 nM.

Original language	English
Pages (from-to)	93-106
Journal	European Journal of Medicinal Chemistry
Volume	43
Issue number	1
DOIs	https://doi.org/10.1016/j.ejmech.2007.02.018
Publication status	Published - 2008

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http://www.sciencedirect.com/science/article/pii/S0223523407001158

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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 2.5e9 mM. Two compounds were found to reduce PrPSc levels to below 30\% relative to an untreated control at 50 nM.",

author = "Kai Guo and Roger Mutter and William Heal and Reddy, \{Tummala Rama Krishna\} 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 Rama Krishna

AU - Cope, Hannah

AU - Pratt, Steven

AU - Thompson, Mark J.

AU - Chen, Beining

PY - 2008

Y1 - 2008

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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 2.5e9 mM. Two compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50 nM.

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DO - 10.1016/j.ejmech.2007.02.018

M3 - Article

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EP - 106

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 1

ER -

Synthesis and Evaluation of a Focused Library of Pyridine Dicarbonitriles Against Prion Disease

Abstract

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