Physicochemical and pharmacokinetic characterization of carbohydrate mimetics

Urinary tract infection by uropathogenic Escherichia coli is one of the most frequent infectious diseases requiring an antibiotic treatment. Since the recurrent exposure to antibiotics leads to the emergence of antibacterial resistance, alternative prevention and treatment strategies are urgently needed.
The interaction of the bacterial lectin FimH with mannosylated glycoproteins on the surface of the bladder mucosa is the initial step triggering the infection. Biaryl α-D-mannopyranosides were identified as potent FimH antagonists preventing this first contact.
The present thesis describes the development of two biaryl mannosides, that are, the biphenyl mannoside bearing a para-carboxylate on the terminal ring of the aglycone and the 5-nitroindolinyl phenyl mannoside, towards drug-likeness. For this purpose, various approaches, such as the introduction of ester or phosphate prodrugs, the replacement of essential substituents with bioisosteres, the optimization of the substitution pattern, or the introduction of aromatic heterocycles, were explored. Several assays addressing the characterization of the physicochemical and in vitro pharmacokinetic properties, i.e. pKa, lipophilicity, aqueous solubility, membrane permeability, plasma protein binding, chemical and metabolic stability, were implemented for the identification of the most successful strategies providing high oral bioavailability, metabolic stability, and sustained renal clearance as major route of drug elimination.
As a result of our thorough studies, two approaches proved most advantageous for the development of orally available FimH antagonists: first, the prodrug approach, i.e. the introduction of an alkyl promoiety masking the carboxylic acid substituent of the biphenyl mannoside or the creation of phosphate monoester prodrugs conferring high aqueous solubility, and second, the replacement of the carboxylic acid with bioisosteres providing optimal physicochemical properties for oral absorption and renal excretion.