Synthesis and biological evaluation of a sialyl lewis X mimic with significantly improved E-selectin inhibition

• Published in: Bioorganic & medicinal chemistry letters 2001-04, Vol.11 (7), p.923-925
• Main Authors: Thoma, Gebhard, Magnani, John L, Patton, John T
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Movement - drug effects; Drug Design; Drug Evaluation, Preclinical; E-Selectin - drug effects; Endothelium - cytology; Glucosamine - chemistry; Humans; Inhibitory Concentration 50; Medical sciences; N-Acetylneuraminic Acid - chemistry; Neutrophils - drug effects; Neutrophils - physiology; Oligosaccharides - chemical synthesis; Oligosaccharides - chemistry; Oligosaccharides - pharmacology; Pharmacology. Drug treatments; Umbilical Veins - cytology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00092-0

The synthesis of the highly potent E-selectin inhibitor 5 is described. Sialyl Lewis X mimic 5 was rationally designed by combining two previously disclosed beneficial sLe x modifications in a single molecule. The compound was found to be 30-fold more potent than sLe x in a static, cell-free equilibrium assay. Furthermore, compound 5 was highly active (IC 50=10 μM) in a dynamic non-equilibrium assay in which sLe x did not inhibit neutrophil rolling at up to 1000 μM. E-Selectin inhibitor 5 is 30-fold more potent than sLe x in a static, cell-free equilibrium assay. It is highly active (IC 50=10 μM) in a dynamic non-equilibrium assay in which sLe x did not inhibit neutrophil rolling at up to 1000 μM.