title: Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity.
abstract: A series of highly potent indole-3-glyoxylamide based antiprion agents was previously characterized, focusing on optimization of structure-activity relationship (SAR) at positions 1-3 of the indole system. New libraries interrogating the SAR at indole C-4 to C-7 now demonstrate that introducing electron-withdrawing substituents at C-6 may improve biological activity by up to an order of magnitude, and additionally confer higher metabolic stability. For the present screening libraries, both the degree of potency and trends in SAR were consistent across two cell line models of prion disease, and the large majority of compounds showed no evidence of toxic effects in zebrafish. The foregoing observations thus make the indole-3-glyoxylamides an attractive lead series for continuing development as potential therapeutic agents against prion disease.
authors: Department of Chemistry, University of Sheffield, Krebs Institute, Brook Hill, Sheffield S3 7HF, UK. m.j.thompson@sheffield.ac.uk
authors: Mark J
authors: MJ
authors: Thompson
authors: Jennifer C
authors: JC
authors: Louth
authors: Steven
authors: S
authors: Ferrara
authors: Matthew P
authors: MP
authors: Jackson
authors: Fiona J
authors: FJ
authors: Sorrell
authors: Edward J
authors: EJ
authors: Cochrane
authors: Joel
authors: J
authors: Gever
authors: Sarah
authors: S
authors: Baxendale
authors: B Michael
authors: BM
authors: Silber
authors: Henry H
authors: HH
authors: Roehl
authors: Beining
authors: B
authors: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D007211:Indoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects*; D011328:Prions / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D007211:Indoles; D011328:Prions