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| Targets |
RORγt Inverse agonist 6 targets the retinoic acid receptor-related orphan receptor gamma t (RORγt), a nuclear receptor transcription factor critical for Th17 cell differentiation and the production of pro-inflammatory cytokines. As an inverse agonist, it binds to RORγt and suppresses its transcriptional activity, thereby inhibiting the Th17-mediated inflammatory pathway. RORγt is a major transcription factor for genes such as IL-17A, IL-22, and IL-23R, which are involved in the pathogenesis of psoriasis and other autoimmune diseases.
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| ln Vitro |
In vitro, RORγt Inverse agonist 6 acts as a RORγt inverse agonist. The compound is used in cell-based assays to investigate its effects on RORγt transcriptional activity and Th17 cell differentiation. It suppresses IL-17A gene expression in vitro. The compound's potency is demonstrated in functional assays measuring inhibition of IL-17A production. Its activity makes it suitable for studying Th17-driven autoimmune diseases. Detailed IC₅₀ values are not specified in the available sources.
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| ln Vivo |
In a mouse pharmacodynamics model, RORγt Inverse Antagonist 6 (compound 43) inhibits the production of the IL-17A gene upon IL-23 stimulation[1]. Compound 43, also known as RORγt Inverse agonist 6, shows better drug exposure (mouse AUC: 1289 ng·h/mL at 1 mg/kg, po)[1]. After oral treatment at the tested dose, RORγt Inverse agonist 6 (compound 43, 30 mg/kg, po, bid) lowers the expression level of IL-17A by 59% in comparison to the vehicle[1].
In vivo, RORγt Inverse agonist 6 (30 mg/kg; oral) inhibits IL-17A expression levels by 59% compared to vehicle control. It suppresses IL-17A gene expression following IL-23 stimulation in vivo. At 1 mg/kg (oral), the compound demonstrates improved compound exposure with an AUC of 1,289 ng·h/mL. These data demonstrate its in vivo efficacy in modulating Th17-driven inflammatory responses. The compound is used in preclinical studies to investigate Th17-mediated inflammation. |
| Enzyme Assay |
Non-cell-based enzyme/receptor binding assays for RORγt Inverse agonist 6 typically involve competitive binding studies using purified RORγt protein. Standard protocols include incubating varying concentrations of the test compound with the RORγt ligand-binding domain and a radiolabeled or fluorescent probe in appropriate buffer systems, followed by separation of bound from free ligand via filtration or fluorescence polarization. Binding affinity (IC₅₀ or Kᵢ values) is calculated using nonlinear regression analysis. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) may also be employed to measure direct binding interactions. The compound is used for studying RORγt inverse agonism.
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| Cell Assay |
Cell-based assays for RORγt Inverse agonist 6 typically utilize reporter gene assays with cells expressing RORγt and a luciferase reporter, or Th17 cell differentiation assays. Standard protocols involve culturing cells in appropriate media at 37°C in 5% CO₂, followed by treatment with varying concentrations of the compound (typically 0.01-10 μM) for 18-24 hours. Reporter gene activity is quantified by luminescence. IL-17A production is measured by ELISA. The compound suppresses IL-17A gene expression in these assays. IC₅₀ values are calculated from dose-response curves.
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| Animal Protocol |
Animal/Disease Models: Mice[1].
Doses: 30 mg/kg. Route of Administration: Orally twice: at 30 min before and 8 h after IL-23 administration. Experimental Results: Inhibited the expression level of IL-17A by 59% compared to the vehicle after the oral administration at the tested dose. In vivo animal studies for RORγt Inverse agonist 6 typically involve oral administration in rodent models (mice or rats). Standard protocols include dosing at 30 mg/kg (oral) to assess effects on IL-17A expression. The compound suppresses IL-17A expression by 59% compared to vehicle control. Pharmacodynamic assessments may include blood sampling for compound exposure analysis (AUC = 1,289 ng·h/mL at 1 mg/kg), tissue collection for cytokine analysis, and monitoring of body weight and general health parameters. All animal studies must comply with institutional ethical guidelines. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties for RORγt Inverse agonist 6 are characterized by oral bioavailability. At 1 mg/kg (oral), the compound demonstrates an AUC of 1,289 ng·h/mL. The compound has a molecular weight of 565.02 g/mol and shows solubility in DMSO (45 mg/mL). For in vivo administration, formulations using 10% DMSO + 90% Corn Oil (2 mg/mL) are recommended. The compound should be stored as powder at -20°C for up to 3 years or in solvent at -80°C for 1 year. Definitive PK parameters such as half-life and Cmax require formal studies.
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| References | |
| Additional Infomation |
RORγt Inverse agonist 6 is a research compound used in preclinical studies to investigate Th17-mediated inflammation. It has been reported to suppress IL-17A expression following IL-23 stimulation in vivo. The compound is supplied for research purposes only and is not intended for human therapeutic applications. It is also referred to as compound 43. The compound is used to study Th17-driven autoimmune diseases. It is not an approved drug and has not undergone clinical trials.
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| Molecular Formula |
C28H29CLN6O5
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|---|---|
| Molecular Weight |
565.0201
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| Exact Mass |
564.188
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| CAS # |
1887161-80-9
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| PubChem CID |
130221704
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| Appearance |
White to off-white solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
1060
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1=C(C#N)C([H])=C([H])C(=C1[H])N([H])C([C]1C([H])([H])N(C([H])([H])C([H])([H])O1)C(N([H])C1C([H])=C([H])C2C([H])(C=1[H])C(N(C([N+]=2C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C1([H])C([H])([H])C1([H])[H])=O)=O)=O |^1:15|
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| InChi Key |
QUTSLTZISBFEOJ-XMMPIXPASA-N
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| InChi Code |
InChI=1S/C28H29ClN6O5/c1-16(2)35-23-8-7-19(11-21(23)26(37)34(28(35)39)14-17-3-4-17)32-27(38)33-9-10-40-24(15-33)25(36)31-20-6-5-18(13-30)22(29)12-20/h5-8,11-12,16-17,24H,3-4,9-10,14-15H2,1-2H3,(H,31,36)(H,32,38)/t24-/m1/s1
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| Chemical Name |
(2R)-2-N-(3-chloro-4-cyanophenyl)-4-N-[3-(cyclopropylmethyl)-2,4-dioxo-1-propan-2-ylquinazolin-6-yl]morpholine-2,4-dicarboxamide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 50 mg/mL (88.49 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.42 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: 2.5 mg/mL (4.42 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7698 mL | 8.8492 mL | 17.6985 mL | |
| 5 mM | 0.3540 mL | 1.7698 mL | 3.5397 mL | |
| 10 mM | 0.1770 mL | 0.8849 mL | 1.7698 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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