Sialyl Lewis X mimics derived from a pharmacophore search are selectin inhibitors with anti-inflammatory activity

The selectins, a family of adhesion receptors involved in leukocyte extravasation, recognize sialyl Lewis X (sLe(x); NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc) and related oligosaccharides. We used conformational energy computations, high field NMR, and structure-function studies to define distance parameters of critical functional groups of sLe(x). This sLe(x) pharmacophore was used to search a three-dimensional data base of chemical structures. Compounds that had a similar spatial relationship of functional groups were tested as inhibitors of selectin binding. Glycyrrhizin, a triterpene glycoside, was identified and found to block selectin binding to sLe(x) in vitro. We substituted different sugars for the glucuronic acids of glycyrrhizin and found the L-fucose derivative to be the most active in vitro and in vivo. A C-fucoside derivative, synthesized on a linker designed for stability and to more closely approximate the original sLe(x) pharmacophore, resulted in an easily synthesized, effective selectin blocker with anti-inflammatory activity.