Antagonists of the myelin-associated glycoprotein: A new class of tetrasaccharide mimics

The tetrasaccharide substructure 1 of the ganglioside GQ1bα shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 1, biphenyl was identified as a feasible replacement for the core disaccharide Galβ(1–3)GalNAc according to saturation transfer difference (STD) NMR and molecular modeling investigations. Using Suzuki coupling, a convergent synthesis of the mimics was achieved. To optimize the yields of the coupling reactions, the catalytic effects of microwave irradiation and conventional heating were compared. The biological evaluation of mimics 3 and 4 was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 3 was clearly enhanced in comparison to the reference trisaccharide 2, despite the former having a much simpler structure. In addition to the improved synthetic feasibility, an increase of the partition coefficient between octanol and water (log P), and therefore a beneficial change in the pharmacokinetic properties of 3 and 4 was achieved.

Simplified mimics of tetrasaccharide 1, where the core disaccharide Galβ(1–3)GalNAc was replaced with a biphenyl, were synthesized and biologically evaluated as inhibitors of the myelin-associated glycoprotein (MAG).Figure optionsDownload as PowerPoint slide