SIALYL-LEWIS-X MIMICS DERIVED FROM A PHARMACOPHORE SEARCH ARE SELECTIN INHIBITORS WITH ANTIINFLAMMATORY ACTIVITY

The selectins, a family of adhesion receptors involved in leukocyte ex travasation, recognize sialyl Lewis X (sLe(x); NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc) and related oligosaccharides. We used confo rmational 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 dimensio nal data base of chemical structures. Compounds that had a similar spa tial relationship of functional groups were tested as inhibitors of se lectin binding. Glycyrrhizin, a triterpene glycoside, was identified a nd found to block selectin binding to sLe(x) in vitro. We substituted different sugars for the glucuronic acids of glycyrrhizin and found th e L-fucose derivative to be the most active in vitro and in vivo. A C- fucoside derivative, synthesized on a linker designed for stability an d to more closely approximate the original sLe(x) pharmacophore, resul ted in an easily synthesized, effective selectin blocker with anti-inf lammatory activity,