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.
NOVARTIS Pharma AG, BAS-350.314, CH-4002 Basel, Switzerland, and Nova Research Services, CH-4143 Dornach, Switzerland. christos.papageorgiou@pharma.novartis.com
C
C
Papageorgiou
R
R
Albert
P
P
Floersheim
M
M
Lemaire
F
F
Bitch
H P
HP
Weber
E
E
Andersen
V
V
Hungerford
M H
MH
Schreier
D000284:Administration, Oral; D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D000090722:Dihydroorotate Dehydrogenase; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D019169:Jurkat Cells / Q000166:cytology / Q000276:immunology; D000077339:Leflunomide; D008070:Lipopolysaccharides / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous / Q000276:immunology*
D000955:Antigens, T-Independent; D000090722:Dihydroorotate Dehydrogenase; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D008070:Lipopolysaccharides; D011720:Pyrazoles; C048761:trinitrophenyl-lipopolysaccharide; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide