title: Structure-activity relationship refinement and further assessment of indole-3-glyoxylamides as a lead series against prion disease.
abstract: Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Louth
authors.forename: Steven
authors.initials: S
authors.lastname: Ferrara
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Sorrell
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Irving
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Cochrane
authors.forename: Anthony J H M
authors.initials: AJ
authors.lastname: Meijer
authors.forename: Beining
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D057166:High-Throughput Screening Assays; D007211:Indoles / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000037:antagonists & inhibitors / Q000378:metabolism; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000737:chemistry
chemical_list: D007211:Indoles; D008024:Ligands; D011328:Prions; D054852:Small Molecule Libraries; D013453:Sulfonylurea Compounds; C032160:glyoxamide