Lead optimization studies on E-selectin antagonists

The interaction of E-, P- and L-selectin with their natural carbohydrate ligands has been shown
to mediate the initial step of the recruitment of leukocytes and to play a crucial role in many
physiological processes and disease states. Therefore, control of the leukocyte-endothelial cell
adhesion process may be useful in cases where excessive recruitment of leukocytes can
contribute to acute or chronic diseases such as stroke, reperfusion injury, psoriasis or
rheumatoid arthritis.
The tetrasaccharide mimetic CGP69669 (41) was early recognized as a lead structure for the
inhibition of E-selectin. In order to improve the lead compound’s pharmacodynamic profile, two
different optimization strategies were envisaged. On the one hand, an unoccupied hydrophobic
patch on the lectin’s surface was targeted with hydrophobic fragments, attached to the galactose
moiety of the lead compound (193, 194, 195/196, 197/198). On the other hand, the ligand’s
entropic costs upon binding were minimized by modifying the cyclohexane moiety (226a-c,
226e-h, 244, 255).