NOVEL SYNTHETIC INHIBITORS OF SELECTIN-MEDIATED CELL-ADHESION - SYNTHESIS OF ENYL)-4-(2-ALPHA-D-MANNOPYRANOSYLOXY)PHENYL]HEXANE (TBC1269)

Reports of a high-affinity ligand for E-selectin, sialyl di-lewis(x) ( sLe(x)Le(x), 1), motivated us to incorporate modifications to previous ly reported biphenyl-based inhibitors that would provide additional in teractions with the protein. These compounds were assayed for the abil ity to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-6 0 cells to E-, P-, and L-selectin fusion proteins. We report that dime ric or trimeric compounds containing multiple components of simple non oligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The e nhanced potency is consistent with additional binding interactions wit hin a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from thi s class of antagonists and is currently under development for use in t he treatment of asthma.