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

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Abstract
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. OJ‐R9188 prevented the binding of human E‐, P‐ and L‐selectin‐IgG fusion proteins to immobilized sialyl Lewisx (sLex)‐pentasaccharide glycolipid, with IC50 values of 4.3, 1.3, and 1.2 μM, respectively. 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‐sLex binding is a promising strategy for the treatment of allergic skin diseases. British Journal of Pharmacology (2001) 134, 1498–1504; doi:10.1038/sj.bjp.0704397