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 its in 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.