%0 Journal Article
%T Analogues of the pan-selectin antagonist rivipansel (GMI-1070).
%A Wagner B
%A Smieško M
%A Jakob RP
%A Mühlethaler T
%A Cramer J
%A Maier T
%A Rabbani S
%A Schwardt O
%A Ernst B
%J Eur J Med Chem
%V 272
%N 0
%D 2024 Jun 5
%M 38728868
%F 7.088
%R 10.1016/j.ejmech.2024.116455
%X The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewisx (sLex, 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLex-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLex and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLex mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.