Potent E-selectin antagonists

Article abstract of DOI:10.1002/1522-2675(20001108)83:11<2893::AID-HLCA2893>3.0.CO;2-G

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' (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).