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

• DOI: 10.1016/j.ejmech.2007.02.018
• Publication Date: 2007-03-13T06:02:54Z
• Authors: Kai Guo; Roger Mutter; William Heal; Tummala R.K. Reddy; Hannah Cope; Steven Pratt; Mark J. Thompson; Beining Chen
• Keywords: Dose-Response Relationship, Drug; Prions; Pyridines; Drug Evaluation, Preclinical; Surface Plasmon Resonance; 01 natural sciences; Prion Diseases; 0104 chemical sciences; Small Molecule Libraries; Kinetics; Mice; Structure-Activity Relationship; Nitriles; Animals; Humans

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 EC(50)s in the range 2.5-9microwo compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50nM.