RT Journal Article
SR Electronic
T1 BMS-190394, a Selectin Inhibitor, Prevents Rat Cutaneous Inflammatory Reactions
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1298
OP 1304
VO 282
IS 3
A1 Gordon Todderud
A1 Xina Nair
A1 Debbie Lee
A1 Julie Alford
A1 Lynda Davern
A1 Paul Stanley
A1 Carol Bachand
A1 Philippe Lapointe
A1 Anne Marinier
A1 Alain Martel
A1 Marcel Menard
A1 John J. Wright
A1 Jurgen Bajorath
A1 Diane Hollenbaugh
A1 Alejandro Aruffo
A1 Kenneth M. Tramposch
YR 1997
UL http://jpet.aspetjournals.org/content/282/3/1298.abstract
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