Potent E-selectin antagonists

In the search for drugs that could control excessive leukocyte extravasatio n, we now report on modifications of the already known potent E-selectin an tagonist 3 containing a cyclohexyllactic acid residue and a glucal-derived building block. Thus, we describe the synthesis and biological evaluation o f a series of derivatives 6 with modified glucal-derived moieties ((CH2NRR2 )-R-1 instead of CH2OH in 3) to explore a hypothetical potential complement ary interaction with E-selectin. However, similar activity profiles of most derivatives 6 and compound 3 do not support such an interaction, but rathe r indicate topological-structure changes of 6 (and 3) in the orientation of the neighboring fucose and galactose due to intramolecular steric interact ions. The most potent E-selectin antagonist 6v showed >50-fold improved E-s electin inhibition compared to the weak selectin ligand sialyl Lewis(x) (sL e(x), 1; IC50 = 1000-1500 muM), but only a 2-fold improvement compared to 3 . Compound 6x was tested in vivo in a murine model of acute inflammation an d found to be as potent as 3 (ED50 = 15 mg/kg).