title: 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.affiliation: R&D Laboratories, Nippon Organon K.K., 5-90. Tomobuchi-cho 1-chome Miyakojima-ku, Osaka 534-0016, Japan. Kuzuhara.Akemi@organon-oka.akzonobel.nl
authors.forename: A
authors.initials: A
authors.lastname: Ikegami-Kuzuhara
authors.forename: T
authors.initials: T
authors.lastname: Yoshinaka
authors.forename: H
authors.initials: H
authors.lastname: Ohmoto
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Saito
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009844:Oligosaccharides / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D010853:Picryl Chloride / Q000008:administration & dosage; D011134:Polysaccharides / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019087:Selectins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D013864:Thioglycolates / Q000008:administration & dosage
chemical_list: D000893:Anti-Inflammatory Agents; D019040:E-Selectin; D016166:Free Radical Scavengers; D007074:Immunoglobulin G; C441961:O-J-R9188; D009844:Oligosaccharides; D019007:P-Selectin; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D013864:Thioglycolates; D019041:L-Selectin; D003907:Dexamethasone; C007789:fucoidan; D003849:Deoxyguanosine; D010853:Picryl Chloride