PYRAZOLE BIOISOSTERES OF LEFLUNOMIDE AS B-CELL IMMUNOSUPPRESSANTS FORXENOTRANSPLANTATION AND CHRONIC REJECTION - SCOPE AND LIMITATIONS

Citation
C. Papageorgiou et al., PYRAZOLE BIOISOSTERES OF LEFLUNOMIDE AS B-CELL IMMUNOSUPPRESSANTS FORXENOTRANSPLANTATION AND CHRONIC REJECTION - SCOPE AND LIMITATIONS, Journal of medicinal chemistry, 41(18), 1998, pp. 3530-3538
Citations number
51
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry Medicinal
ISSN journal
0022-2623
Volume
41
Issue
18
Year of publication
1998
Pages
3530 - 3538
Database
ISI
SICI code
0022-2623(1998)41:18<3530:PBOLAB>2.0.ZU;2-K
Abstract
T-cell immunosuppressant-based therapies efficiently control early gra ft rejection in allotransplantation settings. They fail, however, to p revent those rejection events which are mediated by transplant-induced antibody (Ab) responses such as those involved in xenograft and chron ic 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 o f such Ab, but the drug has pharmacokinetic properties and a therapeut ic window incompatible with transplantation indications. Pyrazole 3, a constrained analogue of 2(Z), was designed and shown to be conformati onally and biologically similar to 2(Z). Further investigations with d erivatives of 3 demonstrated that the pyrazoles had very tight structu re-activity relationships, the only equipotent compound being 3o. Howe ver, in contrast to 2(Z), both 3 and 3o were inactive in vivo due to s hort half-life and drug concentrations lower than the in vitro obtaine d IC50 values, Compound 3o inhibits T-cell-independent Ab production b y a different biochemical mechanism from that of 2(Z) and 3 and may th erefore represent a valuable tool for the identification of new target s for B-cell inhibition.