Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: Parallel synthesis, bioactivity, and in vitro pharmacokinetics

被引：114

作者：

May, Barnaby C. H. ^{[1
]}

Zorn, Julie A.

Witkop, Juanita

Sherrill, John

Wallace, Andrew C.

Legname, Giuseppe

Prusiner, Stanley B.

Cohen, Fred E.

机构：

[1] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA USA

[2] Univ Calif San Francisco, Dept Neurol Cellular & Mol Pharmacol, San Francisco, CA USA

[3] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 01期

关键词：

D O I：

10.1021/jm061045z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.

引用

页码：65 / 73

页数：9

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