FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile

Kleeb, Simon and Pang, Lijuan and Mayer, Katharina and Eris, Deniz and Sigl, Anja and Preston, Roland C. and Zihlmann, Pascal and Sharpe, Timothy and Jakob, Roman P. and Abgottspon, Daniela and Hutter, Aline S. and Scharenberg, Meike and Jiang, Xiaohua and Navarra, Giulio and Rabbani, Said and Smiesko, Martin and Lüdin, Nathalie and Bezençon, Jacqueline and Schwardt, Oliver and Maier, Timm and Ernst, Beat. (2015) FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile. Journal of Medicinal Chemistry, 58 (5). pp. 2221-2239.

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Official URL: http://edoc.unibas.ch/dok/A6357830

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Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl α-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(α-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Rabbani, Said and Schwardt, Oliver and Preston, Roland and Smiesko, Martin and Jiang, Xiaohua and Scharenberg, Meike and Sigl, Anja Carina and Pang, Lijuan and Bezençon, Jacqueline and Maier, Timm and Jakob, Roman Peter and Navarra, Giulio and Sharpe, Timothy and Zihlmann, Pascal and Eris, Deniz and Mayer, Katharina and Kleeb, Simon and Abgottspon, Daniela and Ernst, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 11:18
Deposited On:10 Apr 2015 09:12

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