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.
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 |
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Pages (from-to) | 93-106 |
Journal | European Journal of Medicinal Chemistry |
Volume | 43 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2008 |