Document Detail

APC0576: a novel small molecule, immunosuppressive agent effective in primate models.
MedLine Citation:
PMID:  12792498     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine is a novel synthetic compound with an inhibitory activity on NF-kappaB-dependent gene activation and chemokine synthesis in human endothelial cells. This article describes the effect of APC0576 on T-cell-dependent immune functions in vitro and in vivo in primate models, because NF-kappaB is known to be one of the potent mediators in T-cell activation. METHODS: The effects of APC0576 on interleukin-2 production and proliferative responses in human peripheral blood mononuclear cells were studied under various stimuli with in vitro culture assay. Next, female rhesus monkeys were immunized with tetanus toxoid (TTx), and APC0576 was orally administered for 4 weeks. Serum-specific antibody for TTx was monitored weekly using an enzyme-linked immunosorbent assay, and delayed-type hypersensitivity reaction was examined after 4 weeks of APC0576 treatment. To evaluate the immunosuppressive activity, APC0576 was orally administered for 32 days to rhesus monkeys that received transplants of allogeneic kidney. RESULTS: APC0576 effectively suppressed interleukin-2 production and proliferation in activated human peripheral blood mononuclear cells. Both delayed-type hypersensitivity reaction and specific antibody formation evoked by TTx was significantly and dose-dependently attenuated by 4 weeks treatment of APC0576 without any serious toxicologic signs. Allogeneic kidneys grafted in rhesus monkeys were not rejected and fully functioned during the 32 days of APC0576 treatment, although they were rapidly rejected after the withdrawal of the drug. CONCLUSIONS: A novel, orally available immunosuppressive agent, APC0576, effectively inhibited T-cell-based immune responses both in vitro and in vivo. APC0576 may have potential for a therapeutic agent in clinical organ transplantation and various cytokine-mediated diseases.
Kenji Yuzawa; Atsushi Konishi; Kenji Takehana; Yukio Iino; Akiko Ohnuki; Tsuyoshi Kobayashi; Katashi Fukao; Nobuhiro Ohkohchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  75     ISSN:  0041-1337     ISO Abbreviation:  Transplantation     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-06-06     Completed Date:  2003-06-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1463-8     Citation Subset:  IM    
Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan.
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MeSH Terms
Cyclopropanes / pharmacology*
Dose-Response Relationship, Drug
Hypersensitivity, Delayed / prevention & control
Immunosuppressive Agents / pharmacology*
Interleukin-2 / biosynthesis
Kidney Transplantation
Lymphocyte Activation / drug effects
Macaca mulatta
Models, Animal
NF-kappa B / antagonists & inhibitors*
Pyridines / pharmacology*
Reg. No./Substance:
0/5-((2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-((2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine; 0/Cyclopropanes; 0/Immunosuppressive Agents; 0/Interleukin-2; 0/NF-kappa B; 0/Pyridines

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