FimH Antagonists: Phosphate Prodrugs Improve Oral Bioavailability

Kleeb, Simon and Jiang, Xiaohua and Frei, Priska and Sigl, Anja and Bezençon, Jacqueline and Bamberger, Karen and Schwardt, Oliver and Ernst, Beat. (2016) FimH Antagonists: Phosphate Prodrugs Improve Oral Bioavailability. Journal of Medicinal Chemistry, 59 (7). pp. 3163-3182.

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Official URL: http://edoc.unibas.ch/52923/

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The widespread occurrence of urinary tract infections has resulted in frequent antibiotic treatment, contributing to the emergence of antimicrobial resistance. Alternative approaches are therefore required. In the initial step of colonization, FimH, a lectin located at the tip of bacterial type 1 pili, interacts with mannosylated glycoproteins on the urothelial mucosa. This initial pathogen/host interaction is efficiently antagonized by biaryl α-d-mannopyranosides. However, their poor physicochemical properties, primarily resulting from low aqueous solubility, limit their suitability as oral treatment option. Herein, we report the syntheses and pharmacokinetic evaluation of phosphate prodrugs, which show an improved aqueous solubility of up to 140-fold. In a Caco-2 cell model, supersaturated solutions of the active principle were generated through hydrolysis of the phosphate esters by brush border-associated enzymes, leading to a high concentration gradient across the cell monolayer. As a result, the in vivo application of phosphate prodrugs led to a substantially increased Cmax and prolonged availability of FimH antagonists in urine.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Ernst, Beat and Kleeb, Simon and Jiang, Xiaohua and Frei, Priska and Sigl, Anja Carina and Bezençon, Jacqueline and Schwardt, Oliver
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 11:16
Deposited On:25 Oct 2017 15:22

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