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

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• 作者：Tobias Klein ; Daniela Abgottspon ; Matthias Wittwer ; Said Rabbani ; Janno Herold ; Xiaohua Jiang ; Simon Kleeb ; Christine Lthi ; Meike Scharenberg ; Jacqueline Bezenon ; Erich Gubler ; Lijuan Pang ; Martin Smi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 23, 2010
• 年：2010
• 卷：53
• 期：24
• 页码：8627-8641
• 全文大小：1180K
• 年卷期：v.53,no.24(December 23, 2010)
• ISSN：1520-4804

文摘

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 pili, 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 α-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.