Synthesis and biological evaluation of a potent E-selectin antagonist

An early step of the inflammatory response-the rolling of leukocytes on act ivated endothelial cells-is mediated by selectin/carbohydrate interactions. The tetrasaccharide sialyl Lewis(x) (sLe(x)) 1 is a ligand for E-, P-, and L-selectin and, therefore, serves as a lead structure to develop analogues which allow the control of acute and chronic inflammation. Here we describ e the efficient synthesis (10 linear steps) of the potent sLe(x) mimetic 2. Compared to sLe(x), compound 2 showed a 30-fold improved affinity in a sta tic, cell-free E-selectin-ligand binding assay (IC50 = 36 mu M). These data were confirmed by a marked inhibition in an in vitro cell-cell rolling ass ay which simulates in vivo conditions (IC50 approximate to 40 mu M). The as says are predictive for the in vivo efficacy of test compounds as indicated by a marked inhibitory effect of 2 in a thioglycollate induced peritonitis model of acute inflammation in mice (ED50 approximate to 15 mg/kg).