title: Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics.
abstract: 2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California-San Francisco, San Francisco, California 94158, USA. bmay@ind.ucsf.edu
authors.forename: Barnaby C H
authors.initials: BC
authors.lastname: May
authors.forename: Julie A
authors.initials: JA
authors.lastname: Zorn
authors.forename: Juanita
authors.initials: J
authors.lastname: Witkop
authors.forename: John
authors.initials: J
authors.lastname: Sherrill
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wallace
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Fred E
authors.initials: FE
authors.lastname: Cohen
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D008567:Membranes, Artificial; D009570:Nitriles; D018620:PrPSc Proteins