Pyrazole Bioisosteres of Leflunomide as B-Cell Immunosuppressants for Xenotransplantation and Chronic Rejection: Scope and Limitations
| Autor: | Hans Peter Weber, Valerie Hungerford, Elsebeth Andersen, Francis Bitch, Christos Papageorgiou, Max H. Schreier, Rainer Albert, Michel Lemaire, Philipp Floersheim |
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| Rok vydání: | 1998 |
| Předmět: |
Graft Rejection
Lipopolysaccharides Oxidoreductases Acting on CH-CH Group Donors medicine.medical_treatment Xenotransplantation Transplantation Heterologous Dihydroorotate Dehydrogenase Administration Oral In Vitro Techniques Pyrazole Pharmacology Jurkat Cells Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery medicine Animals Humans Structure–activity relationship Leflunomide B-Lymphocytes Isoxazoles Antigens T-Independent Transplantation Immunoglobulin M chemistry Mechanism of action Immunoglobulin G Injections Intravenous Pyrazoles Molecular Medicine Lymphocyte Culture Test Mixed medicine.symptom Oxidoreductases Cell Division Immunosuppressive Agents Allotransplantation medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 41:3530-3538 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm981028c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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