TAK-779CCR5 antagonists CAS# 229005-80-5 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 229005-80-5 | SDF | Download SDF |
PubChem ID | 183789 | Appearance | Powder |
Formula | C33H39ClN2O2 | M.Wt | 531.13 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | Takeda 779 | ||
Solubility | DMSO : ≥ 25 mg/mL (47.07 mM) H2O : 16.66 mg/mL (31.37 mM; Need ultrasonic and warming) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7H-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium;chloride | ||
SMILES | CC1=CC=C(C=C1)C2=CC3=C(CCCC(=C3)C(=O)NC4=CC=C(C=C4)C[N+](C)(C)C5CCOCC5)C=C2.[Cl-] | ||
Standard InChIKey | VDALIBWXVQVFGZ-UHFFFAOYSA-N | ||
Standard InChI | InChI=1S/C33H38N2O2.ClH/c1-24-7-11-27(12-8-24)28-14-13-26-5-4-6-29(22-30(26)21-28)33(36)34-31-15-9-25(10-16-31)23-35(2,3)32-17-19-37-20-18-32;/h7-16,21-22,32H,4-6,17-20,23H2,1-3H3;1H | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | TAK-779 is a potent and selective nonpeptide antagonist of CCR5 and CXCR3, with a Ki of 1.1 nM for CCR5, and effectively and selectively inhibits R5 HIV-1, with EC50 and EC90 of 1.2 nM and 5.7 nM, respectively, in MAGI-CCR5 cells.In Vitro:TAK-779 is a potent and selective nonpeptide antagonist of CCR5, with a Ki of 1.1 nM, and effectively and selectively inhibits R5 HIV-1, with EC50 and EC90 of 1.2 nM and 5.7 nM, respectively, in MAGI-CCR5 cells. TAK-779 less potently blocks the binding of [125I]-monocyte chemotactic protein 1 to CCR2b in CHO/CCR2b cells, with an IC50 for CCR2b of 27 nM. TAK-779 also completely inhibits the binding of [125I]-RANTES to CHO/CCR5 cells with an IC50 of 1.4 nM. TAK-779 (20 nM) selectively inhibits CCR5-mediated Ca2+-signaling. In addition, TAK-779 shows no inhibition on X4 HIV-1 strains[1]. TAK-779 is an antagonist of CXCR3, and inhibits the migration of T cells but not T cell proliferation[2].In Vivo:TAK-779 (10 mg/kg per day, s.c.) significantly prolongs the allograft survival of the rat intestinal transplantation model. TAK-779 also decreases the number of CD4+ as well as CD8+ T cells in spleen, blood and recipient mesenteric lymph nodes (MLN)[2]. TAK-779 (150 µg per mouse, s.c.) supppresses the development of experimental autoimmune encephalomyelitis (EAE) in myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL/6 mice. TAK-779 decreases the infiltration of CXCR3 and CCR5 bearing leukocytes into the spinal cord. TAK-779 does not alter myelin oligodendrocyte glycoprotein (MOG)-specific immune responses or affect the potential of MOG-specific T cells to transfer experimental autoimmune encephalomyelitis (EAE)[3]. References: |
TAK-779 Dilution Calculator
TAK-779 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 1.8828 mL | 9.4139 mL | 18.8278 mL | 37.6556 mL | 47.0695 mL |
5 mM | 0.3766 mL | 1.8828 mL | 3.7656 mL | 7.5311 mL | 9.4139 mL |
10 mM | 0.1883 mL | 0.9414 mL | 1.8828 mL | 3.7656 mL | 4.7069 mL |
50 mM | 0.0377 mL | 0.1883 mL | 0.3766 mL | 0.7531 mL | 0.9414 mL |
100 mM | 0.0188 mL | 0.0941 mL | 0.1883 mL | 0.3766 mL | 0.4707 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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TAK-779 is a novel, potent and selective small-molecule antagonists of CCR5 with the IC50 value of 1.4nM in binding assay [1].
TAK-779 has been revealed selectively inhibit the binding of [125I]MCP-1 to CCR2b in CHO/CCR2b cells with an IC50 value of 27nM, the value was about 20-fold higher than that for CCR5. In addition, TAK-779 has shown the inhibitory effect on M-troppic HIV-1 (Ba-L strain) replication with the EC50 values of 1.2nM and 3.7nM in MAGI-CCR5 cells and peripheral blood mononuclear cells (PBMCs), respectively. The 50% cytotoxic concentrations (CC50 value) of TAK-779 for MAGI-CCR5 cells and peripheral blood mononuclear cells (PBMCs) are 51μM and >20μM, respectively [1].
References:
[1] Shiraishi M1, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M, Fujino M. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J Med Chem. 2000 May 18;43(10):2049-63.
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Diverse modifications of the 4-methylphenyl moiety of TAK-779 by late-stage Suzuki-Miyaura cross-coupling.[Pubmed:24217712]
Org Biomol Chem. 2014 Jan 7;12(1):177-86.
Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In order to increase the oral bioavailability replacement of the quaternary ammonium structure by a tertiary amine and modification of the 4-methylphenyl moiety were envisaged. Herein, a new synthetic strategy for the development of TAK-779 analogs by late stage diversification is reported. The Suzuki-Miyaura cross-coupling reactions allowed various modifications of the central amide building block 3 at the end of the synthesis leading to compounds 2f and 2h with a promising CCR5 binding affinity.
Synthesis of thiophene-based TAK-779 analogues by C-H arylation.[Pubmed:23642160]
J Org Chem. 2013 Jun 7;78(11):5579-86.
A rapid synthesis of thiophene-based TAK-779 analogues 1 is reported using a late-stage diversification strategy. At the end of the synthesis, the key building block 2, which was prepared in six steps from thiophene, was arylated regioselectively at the alpha-position directly with iodoarenes. Since 2 offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system 2 into 2-aryl-substituted compounds 9. The direct C-H arylation of 2 with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides 1 was synthesized by hydrolysis of 9 and subsequent HATU coupling with primary amines 4.
CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779.[Pubmed:25425280]
Br J Pharmacol. 2015 Apr;172(7):1822-33.
BACKGROUND AND PURPOSE: The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. EXPERIMENTAL APPROACH: Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-112(2:63) ), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. KEY RESULTS: Mutation of Asn-132(3.33) , Phe-207 and Tyr-271(6.51) within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-112(2:63) had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-131(3.32) , Ile-279(6.59) and Tyr-308(7.43) were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. CONCLUSIONS AND IMPLICATIONS: This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential.
HIV-1 clade C envelopes obtained from late stage symptomatic Indian patients varied in their ability towards relative CD4 usages and sensitivity to CCR5 antagonist TAK-779.[Pubmed:21524671]
Virus Res. 2011 Jun;158(1-2):216-24.
The mechanism by which strictly CCR5 using HIV-1 clade C variants exacerbate disease progression in absence of coreceptor switch is not clearly known. We previously reported HIV-1 clade C envelopes (Env) obtained from late stage Indian patients with expanded coreceptor tropism. Here we compared such Envs (having expanded coreceptor tropism) with strictly CCR5 using Envs also obtained from late stage in their capacity to utilize CD4 and CCR5 for productive entry. We found that while envelopes with low CD4 dependence tend to infect primary CD4(+) T cells better than those required optimum CD4 for entry, no significant association was found between low CD4 usage and infectivity of primary CD4(+) T cells by Env-pseudotyped viruses and their sensitivity to CCR5 antagonist TAK-779. Interestingly, Envs that readily infected HeLa cells expressing low CD4 showed relative resistance to T20 indicating that conformational intermediates of these envelopes remained for a shorter period of time than is required for efficient inhibition by T20.