SAR by MS: Discovery of a new class of RNA-binding small molecules for the hepatitis C virus: Internal ribosome entry site IIA subdomain

被引：138

作者：

Seth, PP ^{[1
]}

Miyaji, A ^{[1
]}

Jefferson, EA ^{[1
]}

Sannes-Lowery, KA ^{[1
]}

Osgood, SA ^{[1
]}

Propp, SS ^{[1
]}

Ranken, R ^{[1
]}

Massire, C ^{[1
]}

Sampath, R ^{[1
]}

Ecker, DJ ^{[1
]}

Swayze, EE ^{[1
]}

Griffey, RH ^{[1
]}

机构：

[1] Ibis Therapeut, Carlsbad, CA 92008 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 23期

关键词：

D O I：

10.1021/jm050815o

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole 'hit' 1 with a K-D similar to 100 mu M to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K-D for the RNA target.

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页码：7099 / 7102

页数：4

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