FimH Antagonists for the Oral Treatment of Urinary Tract Infections: From Design and Synthesis to in Vitro and in Vivo Evaluation

被引：160

作者：

Klein, Tobias ^{[1
]}

Abgottspon, Daniela ^{[1
]}

Wittwer, Matthias ^{[1
]}

Rabbani, Said ^{[1
]}

Herold, Janno ^{[1
]}

Jiang, Xiaohua ^{[1
]}

Kleeb, Simon ^{[1
]}

Luethi, Christine ^{[1
]}

Scharenberg, Meike ^{[1
]}

Bezencon, Jacqueline ^{[1
]}

Gubler, Erich ^{[1
]}

Pang, Lijuan ^{[1
]}

Smiesko, Martin ^{[1
]}

Cutting, Brian ^{[1
]}

Schwardt, Oliver ^{[1
]}

Ernst, Beat ^{[1
]}

机构：

[1] Univ Basel, Inst Mol Pharm, Pharmactr, CH-4056 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 24期

基金：

瑞士国家科学基金会;

关键词：

FIMBRIATED ESCHERICHIA-COLI; TYPE-1; FIMBRIAE; MEDIATED ADHESION; RECEPTOR; MANNOSE; INHIBITION; BINDING; AFFINITY; DRUGS; COLONIZATION;

D O I：

10.1021/jm101011y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Urinary tract infection (UTI) by uropathogenic Escherichia coli (UPEC) is one of the most common infections, particularly affecting women. The interaction of FimH, a lectin located at the tip of bacterial pill, with high mannose structures is critical for the ability of UPEC to colonize and invade the bladder epithelium. We describe the synthesis and the in vitro/in vivo evaluation of alpha-D-mannosides with the ability to block the bacteria/host cell interaction. According to the pharmacokinetic properties, a prodrug approach for their evaluation in the UTI mouse model was explored. As a result, an orally available, low molecular weight FimH antagonist was identified with the potential to reduce the colony forming units (CFU) in the urine by 2 orders of magnitude and in the bladder by 4 orders of magnitude. With FimH antagonist 16b, the great potential for the effective treatment of urinary tract infections with a new class of orally available antiinfectives could be demonstrated.

引用

页码：8627 / 8641

页数：15

共 45 条

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