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

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.

Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

“…The ability of leflunomide to inhibit the T cell-dependent immunoglobulin (Ig) class switch from IgM to IgG1 and from IgG1 to IgE is purported to be because of its inhibition of IL4. In ad- dition, leflunomide targets different stages of the B lymphocyte cell cycle (transition from G1 to S phase and entry to G2/M phase) thereby inhibiting proliferation [21,31,33,40,41]. These mechanisms of action are currently being investigated for teriflunomide in our DA rat EAE model.…”

Synthesis and Antimalarial Activity of Substituted Pyrazole Derivatives

“…Some of them are potent non-steroidal analgesic and anti-inflammatory drugs [1−6]. Analogous results were obtained after exposure studies conducted with a group of pyrazole derivatives as immunosuppressive compounds [7].…”

Ixodes ricinus tick salivary gland extract inhibits IL‐10 secretion and CD69 expression by mitogen‐stimulated murine splenocytes and induces hyporesponsiveness in B lymphocytes

“…The tick saliva component that induces unresponsiveness is a potential target for tick control and pathogen transmission. Furthermore, B cell immunosuppressants would be of considerable value in the treatment of autoimmune diseases, such as lupus erythematosus, by restoring B cell tolerance to DNA (36), and in the treatment of chronic allograft and xenograph rejection scenarios during the hyperacute or acute phase where T cells do not participate (37). Efficient B cell immunosuppressants are presently absent in therapeutics.…”

“…© 2003 Blackwell Publishing Ltd, Parasite Immunology, 25,[27][28][29][30][31][32][33][34][35][36][37] …”