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Potent E‐Selectin Antagonists
Author(s) -
Bänteli Rolf,
Herold Peter,
Bruns Christian,
Patton John T.,
Magnani John L.,
Thoma Gebhard
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20001108)83:11<2893::aid-hlca2893>3.0.co;2-g
Subject(s) - chemistry , antagonist , stereochemistry , steric effects , selectin , in vivo , fucose , intramolecular force , pharmacology , biochemistry , galactose , receptor , adhesion , organic chemistry , medicine , microbiology and biotechnology , biology
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 (CH 2 NR 1 R 2 instead of CH 2 OH 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 ; IC 50 =1000 – 1500 μ M ), 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 ( ED 50 =15 mg/kg).