Oral bioavailability of carbohydrate mimetics : an "in vitro" and "in vivo" evaluation

Carbohydrates play a crucial role in metabolism, cell recognition, cell differentiation, and adhesion processes. Therefore, these molecules represent a potent source for the development of new treatments against many different diseases with an unmet medical need. However, compounds of this class have major inherent drawbacks related to their chemical structure. Carbohydrates are complex and hydrophilic structures with a large polar surface area, which commonly results in poor pharmacokinetic (PK) properties including low oral bioavailability and short plasma half-life due to fast renal clearance. To overcome the poor PK properties of the natural ligands, specific structural modifications have to be implemented in the drug development process from the beginning.
Improvements of newly synthesized compounds have to be constantly monitored with in vitro and in vivo PK measurements, allowing a direct feedback for further structural modifications. To this purpose, a PADMET platform (Physicochemical properties, Absorption, Distribution, Metabolism, Elimination, Toxicity) of in vitro assays, addressing different aspects that influence the PK properties of a molecule was developed and optimized. The intestinal absorption is a major hurdle to achieve sufficient oral bioavailability of carbohydrate mimetics and therefore,the focus of this work is set on the permeability of carbohydrate mimetic by passive permeation or active transport.
In this thesis, three different targets for the development of potent lead structures starting from natural carbohydrates are discussed:
• E-selectin is a lectin expressed on endothelial cells upon an inflammatory stimulus and is crucial for the recruitment of leukocytes to the side of inflammation. Therefore, E- selectin has been recognized as a potent target for the treatment of various diseases with an inflammatory component. The carbohydrate epitope recognized by E-selectin is the tetrasaccharide sialyl Lewisx (sLex). For the treatment of chronic inflammatory diseases, an oral administration is of interest. However, the development of an orally bioavailable E-selectin antagonist from sLex is challenging due to its chemical properties. To overcome the hurdle of insufficient intestinal absorption, an ester prodrug strategy and a bioisosteric replacement were followed and further evaluated by in vivo PK studies in mice. The ester prodrug approach resulted in insufficient oral bioavailability but improvement of the apparent plasma half-life, whereas the bioisosteric approach lead to the first orally bioavailable E-selectin antagonist.
• Uropathogenic Eschericha coli (UPEC) are the main cause of urinary tract infections(UTI). UPEC are expressing the virulence factor FimH on the distal tip of type 1 fimbriae, which binds to mannosides on the luminal surface of the bladder to prevent bacteria from being washed out by urine flow. FimH is therefore a promising target for an antiadhesive treatment of UTIs in order to replace current antibiotic treatment strategies. In this work, known biphenyl-α-D-manno-pyranosides were further developed in terms of affinity and in vitro PK properties.
• Sialic acids bound or in free circulation are regulated by sialyltransferases and neuraminidases (NEU). Selective inhibitors for the human neuraminidase NEU3 is of interest to study the physiological and pathophysiological role of neuraminidases and further evaluate the potential to develop therapeutics. Here, the development of specific NEU3 inhibitors, as well as the attempt to optimize their PK properties is reported.