| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Purity: ≥98%
TAK-828F (TAK828F) is a novel, potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonist with binding IC50 of 1.9 nM and reporter gene IC50 of 6.1 nM. TAK-828F shows excellent RORγt isoforms selectivity (>5000-fold selectivity against human RORα and RORβ). TAK-828F showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.
| Targets |
Retinoic acid receptor-related orphan receptor γt (RORγt) [1].
Binding IC₅₀: 1.9 nM (95% CI: 1.6–2.2 nM) [1]. Reporter gene IC₅₀: 6.1 nM (95% CI: 3.7–10 nM) [1]. |
|---|---|
| ln Vitro |
In a TR-FRET-based binding assay, TAK-828F showed potent binding affinity to human RORγt with an IC₅₀ of 1.9 nM (95% CI: 1.6–2.2 nM) [1].
In a reporter gene assay using human Jurkat cells, TAK-828F inhibited RORγt transcriptional activity with an IC₅₀ of 6.1 nM (95% CI: 3.7–10 nM) [1]. TAK-828F demonstrated excellent selectivity against other ROR isoforms, with IC₅₀ values >30,000 nM for both human RORα and RORβ, representing >5,000-fold selectivity [1]. In a panel of 20 other nuclear receptors (including ROR isoforms, GR, AR, ERα, PR, VDR, FXR, LXRα, PPARα/δ/γ, RARα, RXRα, etc.), TAK-828F showed >800-fold selectivity for RORγt in both agonist and antagonist modes [1]. The lipophilicity (log D at pH 7.4) of TAK-828F was 3.53, and the lipophilic ligand efficiency (LLE = reporter pIC₅₀ – log D) was calculated to be 4.68 [1]. |
| ln Vivo |
TAK-828F exhibits a strong and dose-dependent suppression of IL-17A expression in mice with an IL-23-induced cytokine production paradigm (0.3, 1, and 3 mg/kg; oral; bid; 28 days); ED80 is 0.5 mg/kg[1].
Mouse IL-23-Induced Gene Expression Model: In a pharmacodynamic model where IL-23 was administered to mice to induce cytokine expression, oral administration of TAK-828F (0.3, 1, and 3 mg/kg, b.i.d.) showed robust and dose-dependent inhibition of IL-17A expression. The ED₈₀ (dose producing 80% inhibition) was 0.5 mg/kg b.i.d. The compound also demonstrated dose-dependent inhibition of other RORγt-regulated genes such as IL-17F, IL-22, and IL-23 receptor, but had no effect on IFN-γ expression (which is not regulated by RORγt) [1]. Mouse Experimental Autoimmune Encephalomyelitis (EAE) Model: In a mouse model of multiple sclerosis induced by MOG₃₅₋₅₅ immunization, oral administration of TAK-828F (0.3, 1, and 3 mg/kg, b.i.d.) significantly reduced the development of clinical symptoms. At 1 and 3 mg/kg, the inhibition rates were 50% and 44%, respectively, compared to the vehicle control group [1]. Mouse Colitis and Psoriasis Models: TAK-828F also showed in vivo efficacy in an activated T cell transfer mouse colitis model and an IL-23-induced mouse psoriasis model by oral administration [1]. |
| Enzyme Assay |
RORγt Binding Assay (TR-FRET): The binding activity of test compounds to RORγt was measured by a time-resolved fluorescence resonance energy transfer (TR-FRET) method. Histidine-tagged RORγt, a fluorescent-labeled synthetic ligand, and a terbium-labeled anti-histidine tag antibody were used. Test compounds diluted in assay buffer were added to a 384-well plate, followed by RORγt, then the fluorescent-labeled ligand. After incubation, the terbium-labeled antibody was added. Fluorescence intensity was measured (excitation 320 nm, emission 520 nm, delay time 100 μs) using a plate reader. The binding inhibitory rate was calculated [1].
Reporter Gene Assay: Jurkat cells were used to evaluate the functional ability of test compounds to affect RORγt transcriptional activity. Cells were transfected with a reporter vector containing a human IL-17 ROR response element upstream of luciferase and a vector expressing RORγt. After electroporation, cells were plated in 96-well plates and treated with test compounds overnight. Luciferase activity was measured using a detection reagent, and the luminescence level was quantified using a plate reader [1]. |
| Cell Assay |
Reporter Gene Assay (Jurkat Cells): The reporter gene assay described above in Enzyme Assay was performed in human Jurkat cells to evaluate the functional inhibition of RORγt transcriptional activity. This was the primary cell-based assay used to characterize TAK-828F [1].
|
| Animal Protocol |
Animal/Disease Models: IL-23-induced cytokine expression model mouse [1]
Doses: 0.3, 1, 3 mg/kg Route of Administration: Oral; Bid; 28 days Experimental Results: Demonstrated robust and dose-dependent response to IL-17A expression Dependent inhibition (ED80=0.5 mg/kg). Mouse EAE Model: Female C57BL/6 mice were immunized subcutaneously with an emulsion containing 200 μg of MOG₃₅₋₅₅ peptide and 500 μg of killed Mycobacterium tuberculosis H37Ra in Freund’s incomplete adjuvant on day 0. Pertussis toxin (200 ng) was administered intraperitoneally on days 0 and 2. TAK-828F was suspended in 0.5% methylcellulose (0.5% MC) and administered orally twice daily (b.i.d.) from day 0 to day 27 at doses of 0.3, 1, and 3 mg/kg. Vehicle-treated control mice received 0.5% MC solution. Clinical symptoms of EAE were scored daily using a 0–5 scale. The cumulative score was calculated by adding individual scores from day 0 to day 28 [1]. |
| ADME/Pharmacokinetics |
Mouse PK: In mouse cassette-dosing tests, TAK-828F showed favorable pharmacokinetic profiles. At an oral dose of 1 mg/kg, Cmax was 1562 ng/mL, Tmax was 2.3 hours, AUC₀₋₈ₕ was 10076 μg·h/mL, mean residence time (MRT) was 4.1 hours, and oral bioavailability (F) was 96% [1].
|
| Toxicity/Toxicokinetics |
No specific toxicity data for TAK-828F were described in the provided literature. However, the compound’s excellent selectivity (>800-fold over 20 other nuclear receptors) suggests a low risk for off-target toxicities related to nuclear receptor modulation [1].
|
| References | |
| Additional Infomation |
TAK-828F (TAK-828F) is a novel, potent, and selective RORγt inverse agonist that was selected as a clinical candidate for the treatment of Th17-driven autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease [1].
The compound was discovered through a strategy focused on reducing lipophilicity (log D) and optimizing lipophilic ligand efficiency (LLE) to achieve favorable drug-like properties. The final optimization involved replacing the tetrahydroisoquinoline core with a tetrahydronaphthyridine scaffold and modifying the aniline moiety from a trimethylsilyl group to a fluorodimethylindan group [1]. The absolute configuration of TAK-828F was confirmed as (5R) by X-ray crystallographic analysis of its sulfate salt (ORTEP diagram provided). The X-ray co-crystal structure of TAK-828F bound to RORγt (PDB 6BR3) revealed the binding mode, including a hydrogen bond between the NH of the aniline moiety and the backbone carbonyl of Phe377, a hydrogen bond between the carboxylate carbonyl and the NH of Glu379, a water-mediated interaction between the methoxy group and Arg364, and an additional water-mediated interaction between the pyridine nitrogen and Gln286 [1]. |
| Molecular Formula |
C28H32FN3O5
|
|---|---|
| Molecular Weight |
509.569190979004
|
| Exact Mass |
509.232
|
| Elemental Analysis |
C, 66.00; H, 6.33; F, 3.73; N, 8.25; O, 15.70
|
| CAS # |
1854901-94-2
|
| Related CAS # |
1854901-94-2;1854902-31-0 (sulfate); 1854902-24-1 (sulfate hydrate 1:1:1); 1854902-23-0 (sulfate hydrate 2:2:1);
|
| PubChem CID |
118622692
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
3.6
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
37
|
| Complexity |
893
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC1(CCC2=C1C(=CC(=C2)NC(=O)[C@H]3C4=C(CCN3C(=O)C5CC(C5)CC(=O)O)N=C(C=C4)OC)F)C
|
| InChi Key |
ICMFYVOUDGRBLG-VFHHBZAHSA-N
|
| InChi Code |
InChI=1S/C28H32FN3O5/c1-28(2)8-6-16-13-18(14-20(29)24(16)28)30-26(35)25-19-4-5-22(37-3)31-21(19)7-9-32(25)27(36)17-10-15(11-17)12-23(33)34/h4-5,13-15,17,25H,6-12H2,1-3H3,(H,30,35)(H,33,34)/t15-,17+,25-/m1/s1
|
| Chemical Name |
[ cis-3-({(5R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic Acid
|
| Synonyms |
TAK828F; TAK 828F; TAK-828F; 1854901-94-2; TAK-828-F free base; TAK-828; TAK828-F; TAK-828-F;
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9624 mL | 9.8122 mL | 19.6244 mL | |
| 5 mM | 0.3925 mL | 1.9624 mL | 3.9249 mL | |
| 10 mM | 0.1962 mL | 0.9812 mL | 1.9624 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.
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.
(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.
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