From the ganglioside GQ1bα to glycomimetic antagonists of the myelin- associated glycoprotein (MAG)

Abstract

The tetrasaccharide 4, a substructure of ganglioside GQ1bα, shows a remarkable affinity for the myelinassociated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Galβ (1-3)GalNAc, as well as the terminal α (2-3)- and the internal α (2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17. © Schweizerische Chemische Gesellschaft.