Abstract
T-cell immunosuppressant-based therapies efficiently control early graft rejection in allotransplantation settings. They fail, however, to prevent those rejection events which are mediated by transplant-induced antibody (Ab) responses such as those involved in xenograft and chronic allograft rejection. This is mainly due to their inability to block T-cell-independent Ab production against the transplanted organs. The bioactive metabolite 2(Z) of leflunomide (1) inhibits the formation of such Ab, but the drug has pharmacokinetic properties and a therapeutic window incompatible with transplantation indications. Pyrazole 3, a constrained analogue of 2(Z), was designed and shown to be conformationally and biologically similar to 2(Z). Further investigations with derivatives of 3 demonstrated that the pyrazoles had very tight structure-activity relationships, the only equipotent compound being 3o. However, in contrast to 2(Z), both 3 and 3o were inactive in vivo due to short half-life and drug concentrations lower than the in vitro obtained IC50 values. Compound 3o inhibits T-cell-independent Ab production by a different biochemical mechanism from that of 2(Z) and 3 and may therefore represent a valuable tool for the identification of new targets for B-cell inhibition.
MeSH terms
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Administration, Oral
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Animals
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Antigens, T-Independent / immunology
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B-Lymphocytes / drug effects*
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B-Lymphocytes / immunology
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Cell Division / drug effects
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Cell Division / immunology
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Dihydroorotate Dehydrogenase
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Graft Rejection / immunology
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Graft Rejection / prevention & control*
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Humans
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Immunoglobulin G / immunology
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Immunoglobulin M / immunology
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Immunosuppressive Agents* / chemical synthesis
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Immunosuppressive Agents* / chemistry
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Immunosuppressive Agents* / pharmacokinetics
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Immunosuppressive Agents* / pharmacology
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In Vitro Techniques
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Injections, Intravenous
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Isoxazoles / chemistry*
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Isoxazoles / pharmacology
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Jurkat Cells / cytology
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Jurkat Cells / immunology
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Leflunomide
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Lipopolysaccharides / immunology
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Lymphocyte Culture Test, Mixed
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Mice
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Oxidoreductases / antagonists & inhibitors
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Oxidoreductases Acting on CH-CH Group Donors*
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Pyrazoles* / administration & dosage
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Pyrazoles* / chemical synthesis
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Pyrazoles* / pharmacokinetics
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Pyrazoles* / pharmacology
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Structure-Activity Relationship
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Transplantation, Heterologous / immunology*
Substances
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Antigens, T-Independent
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Dihydroorotate Dehydrogenase
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Immunoglobulin G
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Immunoglobulin M
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Immunosuppressive Agents
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Isoxazoles
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Lipopolysaccharides
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Pyrazoles
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trinitrophenyl-lipopolysaccharide
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Oxidoreductases
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Oxidoreductases Acting on CH-CH Group Donors
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Leflunomide