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Low Molecular Weight Antagonists of the Myelin-Associated Glycoprotein: Synthesis, Docking, and Biological Evaluation

2010; American Chemical Society; Volume: 53; Issue: 4 Linguagem: Inglês

10.1021/jm901517k

1520-4804

Stefanie Mesch, Delia Moser, Daniel S. Strasser, Antje Kelm, Brian Cutting, Gianluca Rossato, Angelo Vedani, Hendrik Koliwer‐Brandl, Matthias Wittwer, Said Rabbani, Oliver Schwardt, Sørge Kelm, Beat Ernst,

Axon Guidance and Neuronal Signaling

The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like lectin). In earlier studies, we identified the lead structure 5, which shows a 250-fold improved in vitro affinity for MAG compared to the tetrasaccharide binding epitope of GQ1balpha (1), the best physiological MAG ligand described so far. By modifying the 2- and 5-position, the affinity of 5 could be further improved to the nanomolar range (-->19a). Docking studies to a homology model of MAG allowed the rationalization of the experimental binding properties. Finally, pharmacokinetic parameters (stability in the cerebrospinal fluid, logD and permeation through the BBB) indicate the drug-like properties of the high-affinity antagonist 19a.