Synthesis and biological evaluation of a sialyl lewis X mimic with significantly improved E-selectin inhibition

The synthesis of the highly potent E-selectin inhibitor 5 is described. Sialyl Lewis X mimic 5 was rationally designed by combining two previously disclosed beneficial sLex modifications in a single molecule. The compound was found to be 30-fold more potent than sLex in a static, cell-free equilibrium assay. Furthermore, compound 5 was highly active (IC50=10 μM) in a dynamic non-equilibrium assay in which sLex did not inhibit neutrophil rolling at up to 1000 μM.