title: Low molecular weight antagonists of the myelin-associated glycoprotein: synthesis, docking, and biological evaluation.
abstract: 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.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mesch
authors.forename: Delia
authors.initials: D
authors.lastname: Moser
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.forename: Antje
authors.initials: A
authors.lastname: Kelm
authors.forename: Brian
authors.initials: B
authors.lastname: Cutting
authors.forename: Gianluca
authors.initials: G
authors.lastname: Rossato
authors.forename: Angelo
authors.initials: A
authors.lastname: Vedani
authors.forename: Hendrik
authors.initials: H
authors.lastname: Koliwer-Brandl
authors.forename: Matthias
authors.initials: M
authors.lastname: Wittwer
authors.forename: Said
authors.initials: S
authors.lastname: Rabbani
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Soerge
authors.initials: S
authors.lastname: Kelm
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D012794:Sialic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: C547949:((2,3-difluorobenzyl) 5-fluoroacetamido-9-(4-chlorobenzamido)-3,5,9-trideoxy-d-glycerogalacto-2-nonulopyranosid)onic acid; D018992:Myelin-Associated Glycoprotein; D011994:Recombinant Proteins; D012794:Sialic Acids; D019158:N-Acetylneuraminic Acid