Library synthesis and screening: 2,4-diphenylthiazoles and 2,4-diphenyloxazoles as potential novel prion disease therapeutics

被引：43

作者：

Heal, William ^{[1
]}

Thompson, Mark J. ^{[1
]}

Mutter, Roger ^{[1
]}

Cope, Hannah ^{[1
]}

Louth, Jenny C. ^{[1
]}

Chen, Beining ^{[1
]}

机构：

[1] Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 06期

基金：

英国生物技术与生命科学研究理事会;

关键词：

D O I：

10.1021/jm0612719

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective therapeutics are currently available. In this paper, we report on the synthesis and screening of a small library of 2,4-diphenylthiazol-5-ylamine and 2,4-diphenyloxazol-5-ylamine derivatives as potential novel prion disease therapeutics. Various synthetic strategies were investigated, including a novel phosgene-mediated cyclization of 2-N-benzoylphenylglycinonitrile, and a total of 45 compounds were synthesized. Library members were tested for both binding to prion protein (PrPC) using the surface plasmon resonance technique and for inhibition of PrPSc formation in persistently infected SMB cells. Of the compounds prepared, 15 were found to bind to human PrPC and six showed inhibition of PrPSc formation, displaying EC(50)s between 1.5 and 20 mu M.

引用

页码：1347 / 1353

页数：7

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