From the ganglioside GQ1balpha to glycomimetic antagonists of the myelin-associated glycoprotein (MAG) |
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Authors: | Ernst Beat Schwardt Oliver Mesch Stefanie Wittwer Matthias Rossato Gianluca Vedani Angelo |
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Affiliation: | Institut für Molekulare Pharmazie, Pharmazentrum der Universit?t Basel, Klingelbergstrasse 50, Basel. beat.ernst@unibas.ch |
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Abstract: | The tetrasaccharide 4, a substructure of ganglioside GQ1balpha, shows a remarkable affinity for the myelin-associated 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 Galbeta(1-3)GalNAc, as well as the terminal alpha(2-3)- and the internal alpha(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. |
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