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OtherIMMUNOPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1298-1304;
Gordon Todderud
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Xina Nair
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Debbie Lee
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Julie Alford
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Lynda Davern
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Paul Stanley
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Carol Bachand
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Philippe Lapointe
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Anne Marinier
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Alain Martel
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Marcel Menard
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John J. Wright
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Jurgen Bajorath
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Diane Hollenbaugh
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Alejandro Aruffo
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Kenneth M. Tramposch
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Abstract

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.

Footnotes

  • Send reprint requests to: Gordon Todderud, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Ave., Buffalo, NY 14213.

  • Abbreviations:
    BSA
    bovine serum albumin
    DMSO
    dimethyl sulfoxide
    DTH
    delayed-type hypersensitivity
    FL-1
    fluorescence channel 1
    HBSS
    Hanks’ balanced salt solution
    HTAB
    hexadecyltrimethylammoniumbromide
    Ig
    immunoglobulin
    mO.D. units
    milli optical density units
    MPO
    myeloperoxidase
    PBS
    phosphate-buffered saline
    PMA
    phorbol myristate acetate
    PMN
    polymorphonuclear leukocyte(s)
    Rg
    receptor globulin
    RPA
    reverse passive Arthus
    sLex
    sialyl-Lewisx
    VP
    vascular permeability
    • Received November 26, 1996.
    • Accepted May 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherIMMUNOPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1298-1304;

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OtherIMMUNOPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1298-1304;
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