Subject(s)
B-Lymphocytes/immunology , Cyclosporine/pharmacology , Graft Rejection/immunology , Immunosuppressive Agents/pharmacology , Lymphocyte Activation/drug effects , Pyrazoles/pharmacology , Transplantation, Heterologous/immunology , Aniline Compounds/pharmacology , Animals , Antigens, Heterophile/immunology , B-Lymphocytes/drug effects , Biphenyl Compounds/pharmacology , Cell Division/drug effects , Crotonates , Drug Resistance , Hydroxybutyrates/pharmacology , Isoxazoles/pharmacology , Leflunomide , Lymphocyte Activation/immunology , Lymphoma, B-Cell , Mycophenolic Acid/pharmacology , Nitriles , Primates , Swine , T-Lymphocytes/immunology , Toluidines , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
B-Lymphocytes/drug effects , Graft Rejection/prevention & control , Immunosuppressive Agents , Isoxazoles/chemistry , Oxidoreductases Acting on CH-CH Group Donors , Pyrazoles , Transplantation, Heterologous/immunology , Administration, Oral , Animals , Antigens, T-Independent/immunology , B-Lymphocytes/immunology , Cell Division/drug effects , Cell Division/immunology , Dihydroorotate Dehydrogenase , Graft Rejection/immunology , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , In Vitro Techniques , Injections, Intravenous , Isoxazoles/pharmacology , Jurkat Cells/cytology , Jurkat Cells/immunology , Leflunomide , Lipopolysaccharides/immunology , Lymphocyte Culture Test, Mixed , Mice , Oxidoreductases/antagonists & inhibitors , Pyrazoles/administration & dosage , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
A library of thioamide derivatives of leflunomide 1a and of its bioactive metabolite 1b has been synthesised on solid phase. Thus, para-substituted phenylacetic acids were coupled to TentaGel and were subsequently reacted with aromatic isothiocyanates. Treatment of the resulting enaminothioamides with hydroxylamine led to their simultaneous cyclisation and cleavage from the resin affording 2-25. Their in vitro profiling demonstrated that the amide-thioamide isologous substitution was detrimental of the biological activity.