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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
1998-9-17
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, T-Independent,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin G,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin M,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Isoxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Oxidoreductases,
http://linkedlifedata.com/resource/pubmed/chemical/Oxidoreductases Acting on CH-CH...,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/dihydroorotate dehydrogenase,
http://linkedlifedata.com/resource/pubmed/chemical/leflunomide,
http://linkedlifedata.com/resource/pubmed/chemical/trinitrophenyl-lipopolysaccharide
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
27
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3530-8
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:9719606-Administration, Oral,
pubmed-meshheading:9719606-Animals,
pubmed-meshheading:9719606-Antigens, T-Independent,
pubmed-meshheading:9719606-B-Lymphocytes,
pubmed-meshheading:9719606-Cell Division,
pubmed-meshheading:9719606-Graft Rejection,
pubmed-meshheading:9719606-Humans,
pubmed-meshheading:9719606-Immunoglobulin G,
pubmed-meshheading:9719606-Immunoglobulin M,
pubmed-meshheading:9719606-Immunosuppressive Agents,
pubmed-meshheading:9719606-Injections, Intravenous,
pubmed-meshheading:9719606-Isoxazoles,
pubmed-meshheading:9719606-Jurkat Cells,
pubmed-meshheading:9719606-Lipopolysaccharides,
pubmed-meshheading:9719606-Lymphocyte Culture Test, Mixed,
pubmed-meshheading:9719606-Mice,
pubmed-meshheading:9719606-Oxidoreductases,
pubmed-meshheading:9719606-Oxidoreductases Acting on CH-CH Group Donors,
pubmed-meshheading:9719606-Pyrazoles,
pubmed-meshheading:9719606-Structure-Activity Relationship,
pubmed-meshheading:9719606-Transplantation, Heterologous
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pubmed:year |
1998
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pubmed:articleTitle |
Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations.
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pubmed:affiliation |
NOVARTIS Pharma AG, BAS-350.314, CH-4002 Basel, Switzerland, and Nova Research Services, CH-4143 Dornach, Switzerland. christos.papageorgiou@pharma.novartis.com
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pubmed:publicationType |
Journal Article,
In Vitro
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