Vol. 282, Issue 3, 1298-1304, 1997

BMS-190394, a Selectin Inhibitor, Prevents Rat Cutaneous Inflammatory Reactions

Gordon Todderud, Xina Nair, Debbie Lee, Julie Alford, Lynda Davern, Paul Stanley, Carol Bachand, Philippe Lapointe, Anne Marinier , Alain Martel, Marcel Menard, John J. Wright, Jurgen Bajorath, Diane Hollenbaugh, Alejandro Aruffo and Kenneth M. Tramposch

Bristol-Meyers Squibb Pharmaceutical Research Institute, Buffalo, New York (G.T., X.N., D.L., J.A., L.D., P.S., K.M.T.), Candiac, Quebec, Canada (C.B., P.L., A.M., A.M., M.M.), Wallingford, Connecticut (J.J.W.) and Seattle, Washington. (J.B., D.H., A.A.)

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 T_1/2 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.