PT - JOURNAL ARTICLE AU - Gordon Todderud AU - Xina Nair AU - Debbie Lee AU - Julie Alford AU - Lynda Davern AU - Paul Stanley AU - Carol Bachand AU - Philippe Lapointe AU - Anne Marinier AU - Alain Martel AU - Marcel Menard AU - John J. Wright AU - Jurgen Bajorath AU - Diane Hollenbaugh AU - Alejandro Aruffo AU - Kenneth M. Tramposch TI - BMS-190394, a Selectin Inhibitor, Prevents Rat Cutaneous Inflammatory Reactions DP - 1997 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1298--1304 VI - 282 IP - 3 4099 - http://jpet.aspetjournals.org/content/282/3/1298.short 4100 - http://jpet.aspetjournals.org/content/282/3/1298.full SO - J Pharmacol Exp Ther1997 Sep 01; 282 AB - Selectin binding is the first step in extravasation of leukocytes through the endothelium. Infiltration of leukocytes is a hallmark of an inflammatory response. Blockade of selectin-dependent adhesion, therefore, represents a specific mechanism-based anti-inflammatory strategy. We have used the natural product sulfatide, one of the selectin ligands, as a template to design a novel selectin antagonist. BMS-190394, a structural analog of sulfatide, is an inhibitor of cell binding to P-, E- and L-selectin-Ig fusion proteins. BMS-190394 also inhibits binding mediated by native P-selectin expressed on the surface of activated platelets. Pharmacokinetic analysis of BMS-190394 showed that the compound remained in circulation with a T1/2 of 7 hr, long enough to inhibit the development of an acute inflammatory response. The in vitro activity and pharmacokinetic profile of this selectin-blocking compound led to the determination of itsin vivo anti-inflammatory activity. BMS-190394 was a potent inhibitor of the dermal immune complex-induced reverse passive Arthus reaction in rats when delivered by the i.v. or i.p. route. The ED50 of the compound in the reverse passive Arthus reaction compares favorably to that for dexamethasone. BMS-190394 was also an effective inhibitor of the delayed-type hypersensitivity reaction in the rat. Compared with previous reports of the use of antibodies and complex oligosaccharides to inhibit the activity of the selectins, this low-molecular-weight inhibitor of the selectins presents a novel class of anti-inflammatory agents. The American Society for Pharmacology and Experimental Therapeutics