322761-82-0Relevant academic research and scientific papers
Potent E-selectin antagonists
Baenteli, Rolf,Herold, Peter,Bruns, Christian,Patton, John T.,Magnani, John L.,Thoma, Gebhard
, p. 2893 - 2907 (2007/10/03)
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' (sLex, 1: IC50 = 1000-1500μM), 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).
