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

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.

Method A: malononitrile, piperidine, ethanol were refluxed for 24 h, then under gone aerobic oxidation for 3 h. Method B: malononitrile, piperidine, MWI for 10–120 min at 90 °C, then under gone aerobic oxidation for 3 h.Figure optionsDownload as PowerPoint slide