Potent E‐Selectin Antagonists

In the search for drugs that could control excessive leukocyte extravasation, we now report on modifications of the already known potent E‐selectin antagonist 3 containing a cyclohexyllactic acid residue and a glucal‐derived building block. Thus, we describe the synthesis and biological evaluation of a series of derivatives 6 with modified glucal‐derived moieties (CH₂NR¹R² instead of CH₂OH in 3 ) to explore a hypothetical potential complementary interaction with E‐selectin. However, similar activity profiles of most derivatives 6 and compound 3 do not support such an interaction, but rather indicate topological‐structure changes of 6 (and 3 ) in the orientation of the neighboring fucose and galactose due to intramolecular steric interactions. The most potent E‐selectin antagonist 6v showed >50‐fold improved E‐selectin inhibition compared to the weak selectin ligand sialyl Lewis^x (sLe^x, 1 ; IC₅₀=1000 – 1500 μM ), but only a 2‐fold improvement compared to 3 . Compound 6x was tested in vivo in a murine model of acute inflammation and found to be as potent as 3 (ED₅₀=15 mg/kg).