Pyrazole Bioisosteres of Leflunomide as B-Cell Immunosuppressants for Xenotransplantation and Chronic Rejection:  Scope and Limitations

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.