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.
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
Mark J
MJ
Thompson
Vinciane
V
Borsenberger
Jennifer C
JC
Louth
Katie E
KE
Judd
Beining
B
Chen
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