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 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.
authors.affiliation: Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, UK.
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.forename: Roger
authors.initials: R
authors.lastname: Mutter
authors.forename: William
authors.initials: W
authors.lastname: Heal
authors.forename: Tummala R K
authors.initials: TR
authors.lastname: Reddy
authors.forename: Hannah
authors.initials: H
authors.lastname: Cope
authors.forename: Steven
authors.initials: S
authors.lastname: Pratt
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Beining
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D009570:Nitriles; D011328:Prions; D011725:Pyridines; D054852:Small Molecule Libraries; C023666:pyridine