Studies on Selectin Blockers. 2. Novel Selectin Blocker as Potential Therapeutics for Inflammatory Disorders

• Published in: Journal of medicinal chemistry 1996-05, Vol.39 (10), p.2055-2059
• Main Authors: Wada, Yukihisa, Saito, Tadayuki, Matsuda, Naomi, Ohmoto, Hiroshi, Yoshino, Kohichiro, Ohashi, Masami, Kondo, Hirosato, Ishida, Hideharu, Kiso, Makoto, Hasegawa, Akira
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carbohydrate Sequence; Female; Inflammation - drug therapy; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Oligosaccharides - chemistry; Oligosaccharides - pharmacology; Pharmacology. Drug treatments; Selectins - drug effects; Sulfuric Acid Esters - chemistry; Sulfuric Acid Esters - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950877m

As a part of our studies of selectin blockers, we prepared 1-(2-tetradecylhexadecyl)-3‘-O-sulfo LeX 1 and 1-(2-tetradecylhexadecyl) sLeX 2 and examined their inhibitory activities against natural ligand (sLeX) binding to E-, P-, and L-selectins. Compounds 1 and 2 were 2 times more potent than the sLeX tetrasaccharide toward E-selectin binding and up to 4 times more potent than sLeX toward P- and L-selectin binding. Interestingly, compound 1 provided dose-dependent protective effects against an immunoglobulin E-mediated skin reaction in mouse ears. This protective effect was associated with diminished tissue accumulation of neutrophils in the ear (as assessed by myeloperoxidase). These findings indicate that the modification of sLeX or 3‘-O-sulfo LeX with a “branched anchor”, a 2-tetradecylhexadecyl group, is useful in the design of a more potent selectin blocker, which has broad inhibitory activities toward all selectins.