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

G Thoma; J L Magnani; J T Patton

doi:10.1016/s0960-894x(01)00092-0

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

Bioorg Med Chem Lett. 2001 Apr 9;11(7):923-5. doi: 10.1016/s0960-894x(01)00092-0.

Authors

G Thoma¹, J L Magnani, J T Patton

Affiliation

¹ Novartis Pharma AG, Basel, Switzerland. [email protected]

PMID: 11294392
DOI: 10.1016/s0960-894x(01)00092-0

Abstract

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.

MeSH terms

Cell Movement / drug effects*
Drug Design
Drug Evaluation, Preclinical
E-Selectin / drug effects*
Endothelium / cytology
Glucosamine / chemistry
Humans
Inhibitory Concentration 50
N-Acetylneuraminic Acid / chemistry
Neutrophils / drug effects*
Neutrophils / physiology
Oligosaccharides / chemical synthesis*
Oligosaccharides / chemistry*
Oligosaccharides / pharmacology*
Sialyl Lewis X Antigen
Umbilical Veins / cytology

Substances

E-Selectin
Oligosaccharides
Sialyl Lewis X Antigen
N-Acetylneuraminic Acid
Glucosamine