TAK-779
(Synonyms: Takeda 779) 目录号 : GC37724
An antagonist of CCR5, CXCR3, and CCR2b
Cas No.:229005-80-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | The anti-HIV-1 activities of the test compounds (TAK-779, etc.) are based on the inhibition of virus-induced infectious focus formation in MAGI-CCR5 cells and the reduction of p24 antigen production in PBMCs. In brief, MAGI-CCR5 cells (1 × 104 cells per well) are cultured in a microtiter tray. After a 24-h incubation at 37°C, the culture supernatants are replaced with fresh culture media containing the virus (≈300 focus forming units per well) and various concentrations of the test compounds (TAK-779, etc.). After a 2-day incubation, the cells are fixed and stained with 5-bromo-4-chloro-3-indolyl-β-d-galactosidase. The number of infected (blue) cells is counted microscopically. For the PBMC assays, phytohemagglutinin-stimulated PBMCs (2.5 × 105 cells per 500 μl) are infected with HIV-1 in the presence of various concentrations of the test compounds (TAK-779, etc.). The amounts of the virus used for infection are, depending on the replicability of each strain, generally 1-10 ng of p24 per 2.5 × 105 cells. After an overnight incubation at 37°C, the cells are washed extensively to remove unadsorbed viral particles and are incubated further with culture media containing the same concentrations of the compounds as those used during viral adsorption. On day 6 after viral infection, the culture supernatants are collected and determined for their p24 antigen levels with a sandwich ELISA kit. The cytotoxicities of the compounds are evaluated in parallel with their antiviral activities. They are based on the viability and proliferation of mock-infected cells[1]. |
Animal experiment: | Mice[3]The mice are immunized with MOG and are treated s.c. with TAK-779 or vehicle. The mice (N= 10) are injected s.c. with 150 µg TAK-779 (dissolved in 5% mannitol solution) in a volume of 100 µL, once daily after MOG immunization. TAK-779 injection is started from day 0 after immunization and continued once daily for 22 days. The dose of 150 µg is determined based on the observations in prior experiments that the dose of 50 µg per mouse can not produce inhibition, and a dose of more than 100 µg per mouse is required to produce significant inhibition. The dose of 150 µg per mouse has also been used in other mouse experimental models, and approximately the same dose is used in allograft rejection and asthma models. As a control, an equal volume of PBS containing 5% mannitol is injected daily in the control mice (N= 10)[3]. |
References: [1]. Baba M, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5698-703. | |
TAK-779 is an antagonist of chemokine receptor 5 (CCR5), CCR2b, and CXC chemokine receptor 3 (CXCR3).1,2 It inhibits CCR5 and CXCR3 (IC50s = 236 and 369 nM, respectively, for mouse recombinant receptors expressed in 2B4 T cells) and CCR5 and CCR2b (IC50s = 1.4 and 27 nM, respectively, for human recombinant receptors expressed in CHO cells). TAK-779 inhibits the replication of clinical isolates of R5, but not X4, HIV-1 in human peripheral blood mononuclear cells (PBMCs; EC50s = 1.6-3.5 and >20,000 nM, respectively).1 TAK-779 (250 mg/animal per day) inhibits ovalbumin-induced increases in CCR5, CXCR3, IFN-γ, and TNF-α expression in mouse lung, as well as the number of total cells, lymphocytes, and eosinophils in bronchoalveolar lavage fluid (BALF), in a mouse model of asthma.3 It also increases intestinal allograft survival in a rat model of small intestine transplantation when administered at a dose of 10 mg/kg per day.4
1.Baba, M., Nishimura, O., Kanzaki, N., et al.A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activityProc. Natl. Acad. Sci. USA96(10)5698-5703(1999) 2.Gao, P., Zhou, X.-Y., Yashiro-Ohtani, Y., et al.The unique target specificity of a nonpeptide chemokine receptor antagonist: Selective blockade of two Th1 chemokine receptors CCR5 and CXCR3J. Leukoc. Biol.73(2)273-280(2003) 3.Suzaki, Y., Hamada, K., Nomi, T., et al.A small-molecule compound targeting CCR5 and CXCR3 prevents airway hyperresponsiveness and inflammationEur. J. Respir. J.31(4)783-789(2008) 4.Takama, Y., Miyagawa, S., Yamamoto, A., et al.Effects of a calcineurin inhibitor, FK506, and a CCR5/CXCR3 antagonist, TAK-779, in a rat small intestinal transplantation modelTranspl. Immunol.25(1)49-55(2011)
| Cas No. | 229005-80-5 | SDF | |
| 别名 | Takeda 779 | ||
| Canonical SMILES | C[N+](C)(CC1=CC=C(NC(C2=CC3=CC(C4=CC=C(C)C=C4)=CC=C3CCC2)=O)C=C1)C5CCOCC5.[Cl-] | ||
| 分子式 | C33H39ClN2O2 | 分子量 | 531.13 |
| 溶解度 | DMSO: ≥ 25 mg/mL (47.07 mM); Water: 16.66 mg/mL (31.37 mM and warming) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8828 mL | 9.4139 mL | 18.8278 mL |
| 5 mM | 0.3766 mL | 1.8828 mL | 3.7656 mL |
| 10 mM | 0.1883 mL | 0.9414 mL | 1.8828 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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TAK-779 (Takeda)
Curr Opin Investig Drugs 2001 Mar;2(3):354-6.PMID:11575704doi
TAK-779 is a CCR5 antagonist under investigation by Takeda and Kagoshima University for the potential treatment of HIV [324663], [342114]. TAK-779 inhibits chemokine binding to the CCR5 receptor at nanomolar concentrations. However, it has no effect on the binding of chemokines to the CXCR4 receptor [346835]. A US IND for injectable TAK-779 was filed in june 1999, with Takeda initially planning to commence phase I trials in August 1999. However, the FDA did not clear the IND and recommended that Takeda altered the study protocol to include non-invasive measurement of local toxicities and to evaluate other routes of administration. By September 1999, Takeda had conducted some studies in response to the FDA's recommendations and had made efforts to develop an oral formulation. At this time, the company planned to file a new IND application upon completion of the oral formulation [342114]. In August 1995, Lehman Brothers predicted potential worldwide peak sales of US $300 million in
TAK-779, a nonpeptide CC chemokine receptor antagonist, protects the brain against focal cerebral ischemia in mice
J Cereb Blood Flow Metab 2002 Jul;22(7):780-4.PMID:12142563DOI:10.1097/00004647-200207000-00003.
The effect of a nonpeptide CC chemokine receptor antagonist, TAK-779, on ischemic brain injury resulting from 1-hour middle cerebral artery occlusion followed by 48-hour reperfusion was examined in ddY mice. On intracerebroventricular injection of vehicle or TAK-779, infarct volume in the vehicle-treated group was 44.2 +/- 13.2% of the contralateral hemispheric volume, and TAK-779 (25 and 250 ng/mouse) dose-dependently reduced the infarct volume to 35.0 +/- 12.2% and 31.1 +/- 12.9%, respectively. On intravenous injection, infarct volume in the vehicle-treated group was 32.0 +/- 16.1%, and TAK-779 (5 microg per 20 g body weight) significantly reduced this to 22.0 +/- 10.5%. The results showed for the first time that a nonpeptide chemokine receptor antagonist is protective against ischemic brain injury.
HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice
Arterioscler Thromb Vasc Biol 2005 Dec;25(12):2642-7.PMID:16239591DOI:10.1161/01.ATV.0000192018.90021.c0.
Objective: HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques. Methods and results: TAK-779 treatment of low-density lipoprotein receptor-deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-gamma area. TAK-779-treated animals showed a decreased percentage of CD4+ and CD8+ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals. Conclusions: TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.
The chemokine receptor antagonist, TAK-779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function
Br J Pharmacol 2009 Dec;158(8):2046-56.PMID:20050195DOI:10.1111/j.1476-5381.2009.00528.x.
Background and purpose: The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE). Experimental approach: EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [3H]-thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay. Key results: Treatment with TAK-779 reduced incidence and severity of EAE. It strongly inhibited migration of CXCR3/CCR5 bearing CD4+, CD8+ and CD11b+ leukocytes to the CNS. TAK-779 did not reduce proliferation of anti-MOG T cells, the production of IFN-gamma by T cells or CXCR3 expression on T cells. In addition, TAK-779 did not affect production of IL-12 by antigen-presenting cells, CCR5 induction on T cells and the potential of MOG-specific T cells to transfer EAE. Conclusions and implications: TAK-779 restricted the development of MOG-induced EAE. This effect involved reduced migration of inflammatory cells into the CNS without affecting responses of anti-MOG T cells or the ability of MOG-specific T cells to transfer EAE.
Effects of a calcineurin inhibitor, FK506, and a CCR5/CXCR3 antagonist, TAK-779, in a rat small intestinal transplantation model
Transpl Immunol 2011 Jul;25(1):49-55.PMID:21515370DOI:10.1016/j.trim.2011.04.003.
The effects of FK506, and TAK-779, antagonists of CCR5 and CXCR3, were investigated using a rat intestinal transplantation model. Small intestines from DA rats were heterotopically transplanted into LEW rats. The recipients were treated with FK506 (1mg/kg/day, day 0-5) and TAK-779 (10mg/kg/day, day 0-10). Graft survival and immunological responses to these materials were estimated by mixed lymphocyte reactions and IFN-γ production. The expression of chemokine receptors on lymphocytes was also examined. The average duration of survival was 7.0±0.3, 12.0±1.0, 9.8±0.5 and 18.0±1.5days in the allogeneic, FK506, TAK-779 and the two-drug combined groups, respectively. Cell proliferative responses and IFN-γ production were suppressed to a significant extent in the FK506 group compared with the TAK-779 group. In addition, the two-drug combination showed a tendency for stronger suppression than FK506 alone, correlated with in vivo and histopathological data. The numbers of both CD4(+) and CD8(+) cells were significantly suppressed in the blood of the recipients of both the FK506 and the TAK-779 groups, and in Peyer's patches of the graft of the TAK-779 group, but the FK506 group was not, as evidenced by FACS analysis. In addition, double-staining of graft-infiltrating lymphocytes showed a significant reduction in lymphocyte numbers, expressing CCR5 and CXCR3 in the TAK-779 group, but not evident in the FK506 group, compared to the allogeneic group. While FK506 suppresses cell proliferation and effecter function, it has less effect on the expression of CCR5 and CXCR3 in lymphocytes. Further exploration of the effects of a combined therapy with TAK-779 could represent a novel treatment for intestinal transplantation.