Synthesis and Evaluation of a Focused Library of Pyridine Dicarbonitriles Against Prion Disease
Reddy, Tummala Rama Krishna
Thompson, Mark J.
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.