Journal of medicinal and pharmaceutical chemistry 2010-12-23

FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation.

Tobias Klein, Daniela Abgottspon, Matthias Wittwer, Said Rabbani, Janno Herold, Xiaohua Jiang, Simon Kleeb, Christine Lüthi, Meike Scharenberg, Jacqueline Bezençon, Erich Gubler, Lijuan Pang, Martin Smiesko, Brian Cutting, Oliver Schwardt, Beat Ernst

文献索引：J. Med. Chem. 53 , 8627-41, (2010)

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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 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, the great potential for the effective treatment of urinary tract infections with a new class of orally available antiinfectives could be demonstrated.