Antagonists of the myelin-associated glycoprotein: a new class of tetrasaccharide mimics.
The tetrasaccharide substructure 1 of the ganglioside GQ1balpha 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 Galbeta(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 (logP), and therefore a beneficial change in the pharmacokinetic properties of 3 and 4 was achieved.
Schwizer
Daniel
D
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Gäthje
Heiko
H
Kelm
Soerge
S
Porro
Michele
M
Schwardt
Oliver
O
Ernst
Beat
B
D000818:Animals; D002240:Carbohydrate Sequence; D066298:In Vitro Techniques; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000737:chemistry / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009416:Nerve Regeneration / Q000187:drug effects; D000070798:Nogo Proteins; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D000070798:Nogo Proteins; D009844:Oligosaccharides