TAK-779

Alias: TAK-779 Chloride; TAK779; TAK 779

Cat No.:V4592 Purity: ≥98%

COA Product Data Instructions for use SDS

TAK-779 Chemical Structure CAS No.: 229005-80-5
Product category: CCR

This product is for research use only, not for human use. We do not sell to patients.

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Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

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Nature 597, 119–125 (2021)

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J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

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Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

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MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

TAK-779 (TAK779) is a novel, potent and selective nonpeptide antagonist of CCR5 [C-C chemokine receptor type 5 (CCR5) receptor] and CXCR3 with potential anticancer, immunomodulatory and antiinflammatory activities. It efficiently and selectively inhibits R5 HIV-1 in MAGI-CCR5 cells, with EC50 and EC90 of 1.2 nM and 5.7 nM, respectively, and inhibits CCR5 with a Ki of 1.1 nM. It may be possible to treat HIV infection with TAK-779. The incidence and severity of experimental autoimmune encephalomyelitis were decreased by TAK-779 treatment. It significantly reduced the migration of leukocytes carrying CD4+, CD8+, and CD11b+ markers to the central nervous system (CNS). TAK-779 had no effect on T cell production of IFN-gamma, T cell expression of CXCR3, or the proliferation of anti-myelin oligodendrocyte glycoprotein T cells. TAK-779 also had no effect on antigen-presenting cells' IL-12 production, T cells' induction of CCR5, or the ability of myelin oligodendrocyte glycoprotein-specific T cells to spread experimental autoimmune encephalomyelitis.

Biological Activity I Assay Protocols (From Reference)

Targets

MIP-1α-CCR5 ( IC50 = 1 nM ); MIP-1β-CCR5 ( IC50 = 1 nM ); RANTES-CCR5 ( IC50 = 1.4 nM ); MCP-1-CCR2b ( IC50 = 27 nM ); R5 HIV-1 (Ba-L) ( EC50 = 1.2 nM ); R5 HIV-1 (Ba-L) ( EC90 = 5.7 nM ); R5 HIV-1 (Ba-L) ( EC50 = 3.7 nM ); R5 HIV-1 (Ba-L) ( EC90 = 12.8 nM ); R5 HIV-1 (KK) ( EC50 = 1.6 nM ); R5 HIV-1 (KK) ( EC90 = 20.8 nM ); R5 HIV-1 (HHA) ( EC50 = 3.2 nM ); R5 HIV-1 (HHA) ( EC90 = 7.5 nM ); R5 HIV-1 (CTV) ( EC50 = 3.5 nM ); R5 HIV-1 (CTV) ( EC90 = 27 nM ); mCXCR3( IC50 = 369 nM )

ln Vitro

TAK-779 deters R5 HIV-1 in MAGI-CCR5 cells. It is a strong and selective nonpeptide antagonist of CCR5, with a Ki of 1.1 nM, with an effective and selective EC50 and EC90 of 1.2 nM and 5.7 nM, respectively. In CHO/CCR2b cells, TAK-779 less effectively inhibits the binding of [¹²⁵I]-monocyte chemotactic protein 1 to CCR2b, with an IC50 of 27 nM for CCR2b. With an IC50 of 1.4 nM, TAK-779 also totally prevents [¹²⁵I]-RANTES from binding to CHO/CCR5 cells. CCR5-mediated Ca²⁺-signaling is specifically inhibited by TAK-779 (20 nM). Furthermore, on X4 HIV-1 strains, TAK-779 exhibits no inhibition[1]. As an antagonist of CXCR3, TAK-779 prevents T cell migration but not proliferation[2].

ln Vivo

TAK-779 (10 mg/kg daily, s.c.) considerably increases the rat intestinal transplantation model's allograft survival. Additionally, TAK-779 reduces the quantity of CD4⁺ and CD8⁺ T cells in the recipient's mesenteric lymph nodes (MLN), blood, and spleen[2]. TAK-779 (150 µg/mouse, s.c.) inhibits the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice that have been immunized against myelin oligodendrocyte glycoprotein (MOG). TAK-779 reduces the amount of leukocytes that carry CXCR3 and CCR5 infiltrating the spinal cord. TAK-779 has no effect on immune responses specific to myelin oligodendrocyte glycoprotein (MOG) or on the ability of T cells specific to MOG to transmit experimental autoimmune encephalomyelitis (EAE)[3].

Cell Assay

The test compounds' (TAK-779, etc.) anti-HIV-1 activities are predicated on the suppression of p24 antigen production in PBMCs and the inhibition of virus-induced infectious focus formation in MAGI-CCR5 cells. To put it briefly, MAGI-CCR5 cells are grown in a microtiter tray with 1 × 10⁴ cells per well. The culture supernatants are replaced with new culture media containing the virus (approximately 300 focus forming units per well) and different concentrations of the test compounds (TAK-779, etc.) after a 24-hour incubation at 37°C. Following a two-day incubation period, 5-bromo-4-chloro-3-indolyl-β-d-galactosidase is used to fix and stain the cells. Microscopically, the number of infected (blue) cells is counted. In the PBMC assays, in different concentrations of the test compounds (TAK-779, etc.), HIV-1 is infected into phytohemagglutinin-stimulated PBMCs (2.5 × 10⁵ cells per 500 μl). The virus used for infection typically contains 1–10 ng of p24 per 2.5 × 10⁵ cells, depending on how replicable each strain is. The cells are first cultured with culture media containing the same concentrations of the compounds used during viral adsorption, and then they are subjected to a thorough washing process to remove any remaining viral particles, all while maintaining a 37°C incubation period. The culture supernatants are obtained on day 6 following viral infection, and using a sandwich ELISA kit, the p24 antigen levels are ascertained. The compounds' cytotoxicities and antiviral properties are assessed simultaneously. Their foundation lies in the survival and growth of simulated infected cells [1].

Animal Protocol

Mice: The mice receive a TAK-779 or vehicle injection in addition to their MOG immunization. After receiving the MOG immunization, the mice (N = 10) are given one daily subcutaneous injection of 150 µg TAK-779 (dissolved in 5% mannitol solution) in a volume of 100 µL. Starting on the first day following immunization, TAK-779 injections are administered once a day for 22 days. Based on the findings of previous studies, which showed that a dose of more than 100 µg per mouse is needed to produce significant inhibition, the dose of 150 µg was chosen. A dose of 50 µg per mouse was found to be ineffective. In addition to being used in asthma and allograft rejection models, the dose of 150 µg per mouse has also been utilized in other mouse experimental models. The control mice (N = 10) receive a daily injection of an equivalent volume of PBS containing 5% mannitol as a control[3].

References

[1]. 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.

[2]. 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.

[3]. 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.

[4]. The unique target specificity of a nonpeptide chemokine receptor antagonist: selective blockade of two Th1 chemokine receptors CCR5 and CXCR3. J Leukoc Biol. 2003 Feb;73(2):273-80.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C33H39CLN2O2
Molecular Weight	531.127968072891
Exact Mass	530.27
Elemental Analysis	C, 74.63; H, 7.40; Cl, 6.67; N, 5.27; O, 6.02
CAS #	229005-80-5
Related CAS #	229005-80-5 (Cl); 263765-56-6 (cation)
Appearance	White to beige solid powder
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-]
InChi Key	VDALIBWXVQVFGZ-UHFFFAOYSA-N
InChi Code	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
Chemical Name	dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7H-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium;chloride
Synonyms	TAK-779 Chloride; TAK779; TAK 779
HS Tariff Code	2934.99.9001
Storage	Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)	DMSO: ≥ 25 mg/mL (~47.1 mM) H2O: ~16.7 mg/mL (~31.4 mM)
Solubility (In Vivo)	Solubility in Formulation 1: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More Solubility in Formulation 3: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 50 mg/mL (94.14 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.)

Solubility (In Vitro)

DMSO: ≥ 25 mg/mL (~47.1 mM)
H2O: ~16.7 mg/mL (~31.4 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

View More

Solubility in Formulation 3: ≥ 2.58 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 4: 50 mg/mL (94.14 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		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

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

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In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Biological Data

Characterization of CHO/CCR5 cells and inhibitory effect of TAK-779 on [125I]-RANTES binding to the cells. Proc Natl Acad Sci U S A . 1999 May 11;96(10):5698-703.
Inhibitory effects of TAK-779 on chemokine binding to CCR1-, CCR2b-, CCR3-, or CCR4-expressing CHO cells. Proc Natl Acad Sci U S A . 1999 May 11;96(10):5698-703
TAK-779 treatment did not affect myelin oligodendrocyte glycoprotein (MOG)-specific immune responses. Br J Pharmacol . 2009 Dec;158(8):2046-56.
TAK-779 treatment inhibited cellular infiltration into the spinal cord of mice. Br J Pharmacol . 2009 Dec;158(8):2046-56.
TAK-779 treatment decreased the infiltration of CXCR3 and CCR5 bearing leukocytes into the spinal cord. Br J Pharmacol . 2009 Dec;158(8):2046-56.