Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease

J Med Chem. 2009 Dec 10;52(23):7503-11. doi: 10.1021/jm900920x.

Mark J Thompson ¹, Vinciane Borsenberger, Jennifer C Louth, Katie E Judd, Beining Chen

Affiliations

Affiliation

1 Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.

PMID: 19842664 DOI: 10.1021/jm900920x

Abstract

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.

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