FimH Antagonists: Phosphate Prodrugs Improve Oral Bioavailability.

Kleeb S; Jiang X; Frei P; Sigl A; Bezençon J; Bamberger K; Schwardt O; Ernst B

doi:10.1021/acs.jmedchem.5b01923

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Journal article

FimH Antagonists: Phosphate Prodrugs Improve Oral Bioavailability.

Kleeb S Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Jiang X Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Frei P Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Sigl A Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Bezençon J Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Bamberger K Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Schwardt O Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
Ernst B Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.

2016-03-10

Published in:

Journal of medicinal chemistry. - 2016

Structure-Activity Relationship

English 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.

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