Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease.
Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective curative therapy currently exists. We report here the synthesis of a library of indole-3-glyoxylamides and their evaluation as potential antiprion agents. A number of compounds demonstrated submicromolar activity in a cell line model of prion disease together with a defined structure-activity relationship, permitting the design of more potent compounds that effected clearance of scrapie in the low nanomolar range. Thus, the indole-3-glyoxylamides described herein constitute ideal candidates to progress to further development as potential therapeutics for the family of human prion disorders.
Thompson
Mark J
MJ
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
Borsenberger
Vinciane
V
Louth
Jennifer C
JC
Judd
Katie E
KE
Chen
Beining
B
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000588:Amines / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D017096:Prion Diseases / Q000188:drug therapy / Q000473:pathology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000577:Amides; D000588:Amines; D007211:Indoles; D054852:Small Molecule Libraries; C030374:indole