Synthesis and biological evaluation of a sialyl Lewis X mimic with significantly improved E-selectin inhibition.
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 (IC50 = 10 microM) in a dynamic non-equilibrium assay in which sLe(x) did not inhibit neutrophil rolling at up to 1000 microM.
Thoma
G
G
Novartis Pharma AG, Basel, Switzerland. gebhard.thoma@pharma.novartis.com
Magnani
J L
JL
Patton
J T
JT
D002465:Cell Movement / Q000187:drug effects*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019040:E-Selectin / Q000187:drug effects*; D004727:Endothelium / Q000166:cytology; D005944:Glucosamine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D000080506:Sialyl Lewis X Antigen; D014471:Umbilical Veins / Q000166:cytology
D019040:E-Selectin; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D019158:N-Acetylneuraminic Acid; D005944:Glucosamine