Therapeutic potential of a novel synthetic selectin blocker, OJ-R9188, in allergic dermatitis.

Abstract

1. We investigated the ability of a newly synthesized sugar derivative, OJ-R9188, [N-(2-tetradecylhexadecanoyl)-O-(L-alpha-fucofuranosyl)-D-seryl]-L-glutamic acid 1-methylamide 5-L-arginine salt, to block binding of selectins to their ligands in vitro and inhibit the infiltration of leukocytes in vivo. 2. OJ-R9188 prevented the binding of human E-, P- and L-selectin-IgG fusion proteins to immobilized sialyl Lewis(x) (sLe(x))-pentasaccharide glycolipid, with IC(50) values of 4.3, 1.3, and 1.2 microM, respectively. 3. In a mouse model of thioglycollate-induced peritonitis, OJ-R9188 at 10 mg kg(-1), i.v. inhibited neutrophil accumulation in the peritoneal cavity. In the IgE-mediated skin reaction, OJ-R9188 at 3 and 10 mg kg(-1), i.v. significantly inhibited extravasation of neutrophils and eosinophils into the inflammatory sites and at 10 mg kg(-1), i.v. also inhibited infiltration caused by picryl chloride-induced delayed-type hypersensitivity in mice. These results suggest that OJ-R9188 may be a useful selectin blocker, with activity against human and mouse E-, P- and L-selectins in vitro and in vivo, and that blocking selectin-sLe(x) binding is a promising strategy for the treatment of allergic skin diseases.

• Authors: A Ikegami-Kuzuhara, T Yoshinaka, H Ohmoto, Y Inoue, T Saito
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 134 Issue 7 Pg. 1498-504 (Dec 2001) ISSN: 0007-1188 [Print] England
• PMID: 11724756 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• E-Selectin
• Free Radical Scavengers
• Immunoglobulin G
• O-J-R9188
• Oligosaccharides
• P-Selectin
• Polysaccharides
• Recombinant Fusion Proteins
• Selectins
• Sialyl Lewis X Antigen
• Thioglycolates
• L-Selectin
• Dexamethasone
• fucoidan
• Deoxyguanosine
• Picryl Chloride

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Binding, Competitive (drug effects)
• Deoxyguanosine (analogs & derivatives, pharmacology, therapeutic use)
• Dermatitis (immunology, metabolism, prevention & control)
• Dexamethasone (pharmacology)
• Dose-Response Relationship, Drug
• E-Selectin (metabolism)
• Free Radical Scavengers (pharmacology, therapeutic use)
• Humans
• Hypersensitivity, Delayed (chemically induced, metabolism, prevention & control)
• Immunoglobulin G (metabolism)
• L-Selectin (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Oligosaccharides (metabolism)
• P-Selectin (metabolism)
• Peritonitis (chemically induced, metabolism, prevention & control)
• Picryl Chloride (administration & dosage)
• Polysaccharides (pharmacology)
• Recombinant Fusion Proteins (metabolism)
• Selectins (metabolism)
• Sialyl Lewis X Antigen
• Thioglycolates (administration & dosage)