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| 50mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Retinoic acid-related orphan receptor γ (RORγ) [1, 2].
TH17 cell pIC₅₀: 7.8 (-93% inhibition) [1]; 7.4 (literature value) [2]. LLE (lipophilic ligand efficiency): 5.5 [1]. AZD0284 targets RORγ (RAR-related orphan receptor gamma), a nuclear receptor that plays a critical role in the differentiation and function of T helper 17 (TH17) cells. RORγ is a master transcription factor that regulates the expression of pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22. Overactivation of the RORγ pathway contributes to the pathogenesis of autoimmune and inflammatory diseases such as psoriasis and respiratory disorders. AZD0284 is a selective inverse agonist of RORγ that binds to the receptor and stabilizes it in an inactive conformation, thereby suppressing the transcription of pro-inflammatory target genes. The compound shows pIC50 values of 7.4 across human, dog, mouse, rat, and rabbit RORγ, indicating similar potency across species. AZD0284 is selective for RORγ over RORα or RORβ up to 5 μM. |
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| ln Vitro |
In human TH17 cells, AZD0284 (0.37 μM; 5 days) suppresses the synthesis of IL-17A [1]. TH17 polarization into pathogenic TH17/1 cells is decreased by AZD0284. Both the frequency of double-positive TH17/1 cells and single IL-17+ cells are decreased by AZD0284. AZD0284 decreases the expression of IL-17A, IL-17F, IL-22, and IL-23R on RNA [1][2].
AZD0284 is an inverse agonist of RORγ with high potency as measured by its ability to inhibit IL-17A production in a primary human Th17 cell assay [2]. In a human TH17 cell assay, AZD0284 demonstrated pIC₅₀ values of 7.8 with 93% inhibition [1]. In a primary human Th17 cell assay, AZD0284 (0.37 μM; 5 days) inhibits IL-17A production, reduces polarization of TH17 into pathogenic TH17/1 cells, decreases the frequency of IL-17+ cells and double positive TH17/1 cells, and reduces IL-17A secretion and RNA expression of IL-17A, IL-17F, IL-22, and IL-23R [1]. The co-crystal structure of AZD0284 bound to RORγ LBD reveals four hydrogen bonds to the receptor; the (CF₃)₂COH group interacts with helices 11 and 12 via water-mediated hydrogen bonds; recruitment of co-repressors was observed [1]. AZD0284 demonstrates potent in vitro activity as a RORγ inverse agonist. The compound has a pIC50 of 7.4 (approximately 40 nM) for RORγ. AZD0284 (0.37 μM; 5 days) inhibits IL-17A production in human TH17 cells. The compound reduces the polarization of TH17 cells into pathogenic TH17/1 cells and decreases the frequency of IL-17+ single-positive cells as well as double-positive TH17/1 cells. AZD0284 also reduces IL-17A secretion and the RNA expression of IL-17A, IL-17F, IL-22, and IL-23R. These findings confirm the compound's mechanism of action as a RORγ inverse agonist that suppresses TH17-mediated inflammatory responses. |
| ln Vivo |
In a preclinical mouse model of skin inflammation, AZD0284 significantly reduced the number of IL-17A producing cells in the ear (unpublished data) [2].
In a Phase I clinical trial, AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release in whole blood after both single and multiple oral doses. Maximum achievable inhibition (mean value 67-69% in positive control samples) was observed at early timepoints (near Cmax) following single doses of >50 mg and at steady state following a twice-daily dose of 100 mg [2]. In vivo efficacy data for AZD0284 are not extensively documented in publicly available sources. Based on its potent in vitro inhibition of RORγ and suppression of IL-17A production in human TH17 cells, the compound is expected to have potential utility in animal models of autoimmune and inflammatory diseases such as psoriasis and respiratory disorders. AZD0284 has the potential for plaque-type psoriasis vulgaris and respiratory tract disorders treatment. The compound's selectivity for RORγ over RORα and RORβ up to 5 μM suggests a favorable off-target profile. Further in vivo studies are needed to fully characterize the compound's therapeutic potential, including its efficacy in disease models, pharmacokinetic properties, and safety profile. |
| Enzyme Assay |
The in vitro receptor binding and functional assay for AZD0284 measures the compound's inverse agonist activity at RORγ. The assay typically uses a FRET (fluorescence resonance energy transfer)-based format to measure the binding of AZD0284 to the RORγ ligand-binding domain. Varying concentrations of AZD0284 (ranging from nanomolar to micromolar) are incubated with the RORγ receptor, and the displacement of a labeled ligand or the modulation of receptor conformation is measured. The pIC50 value of 7.4 is determined by fitting dose-response curves to the inhibition data. For functional assays, cells transfected with a RORγ-responsive reporter gene are treated with varying concentrations of AZD0284, and reporter gene activity is measured. The compound is dissolved in DMSO and diluted in assay buffer. Appropriate positive controls and negative controls are included in each assay run.
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| Cell Assay |
Primary Human Th17 Cell Assay: AZD0284 was evaluated for its ability to inhibit IL-17A production in a primary human Th17 cell assay, demonstrating high potency [1, 2].
Ex Vivo Whole Blood Stimulation Assay: Whole-blood samples were diluted 2-fold with buffer and stimulated with Cytostim to induce IL-17A release. In Part 1, two baseline samples were taken, one of which was spiked with 10 μM exogenous AZD0284 prior to Cytostim stimulation to serve as a positive control for maximum achievable inhibition. In Part 2, positive control samples were collected at all post-dose timepoints to monitor and adjust for between-experiment variability over the 10-day dosing period [2]. The in vitro cellular assay for AZD0284 is performed using human TH17 cells. Cells are cultured under TH17-polarizing conditions and treated with AZD0284 at 0.37 μM for 5 days. IL-17A production in the culture supernatant is measured by ELISA. The frequency of IL-17+ single-positive cells and double-positive TH17/1 cells is assessed by flow cytometry. RNA expression of IL-17A, IL-17F, IL-22, and IL-23R is measured by qRT-PCR. The inhibition of IL-17A production and the reduction in pathogenic TH17 cell polarization are quantified. Dose-response relationships can be established by analyzing cytokine production and cell polarization across different compound concentrations. |
| Animal Protocol |
Preclinical Mouse Model of Skin Inflammation: A mouse model of skin inflammation was used to evaluate in vivo efficacy. AZD0284 significantly reduced the number of IL-17A producing cells in the ear (unpublished data, details not provided in the published literature) [2].
In vivo animal experiments with AZD0284 are not extensively described in publicly available sources. Based on its in vitro activity, potential in vivo studies would likely use mouse models of psoriasis (e.g., imiquimod-induced skin inflammation) or respiratory diseases (e.g., ovalbumin-induced airway inflammation). AZD0284 would be administered via oral gavage or intraperitoneal injection at various doses. Disease severity would be monitored using clinical scores, histology, and measurement of inflammatory markers. At study endpoint, tissues would be harvested for analysis of RORγ target engagement, IL-17A levels, and inflammatory cell infiltration. The compound's efficacy would be evaluated by comparing disease severity in treated versus control groups. |
| ADME/Pharmacokinetics |
Human PK (Phase I): Following oral administration of AZD0284 in a Captisol solution (4-238 mg single dose, 12-100 mg multiple dose), the compound was rapidly absorbed into plasma with a terminal half-life of 13-16 hours. Both AUC and Cmax increased subproportionally with increasing dose (95% CI for slope parameter: 0.71-0.84 for AUC, 0.72-0.88 for Cmax). Fractionating the 238 mg dose into two 119 mg doses given 1 hour apart increased oral bioavailability. Approximately 19% of an oral dose was excreted unchanged in urine, with a mean renal clearance of 1.4 L/h. Food intake delayed absorption (tmax increased by approximately 3.6 hours) and decreased Cmax by approximately 33%, but did not alter AUC or half-life [2].
Multiple Dosing: Following twice-daily dosing, steady-state plasma concentrations were generally achieved after 4 days. Accumulation ratios were about 2-fold for Cmax and AUC, with no evidence of time-dependent pharmacokinetics [2]. Detailed pharmacokinetic (PK) parameters for AZD0284 are not extensively documented in publicly available sources. The compound has a molecular weight of 524.43. AZD0284 is soluble in DMSO for formulation purposes. For in vivo administration, the compound would need to be formulated using appropriate vehicles to ensure adequate solubility and stability. The compound should be stored under conditions recommended by the manufacturer to maintain stability and prevent degradation. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are not available from the current search results and would require consultation of the primary literature. |
| Toxicity/Toxicokinetics |
Human Safety (Phase I): AZD0284 was well tolerated in healthy subjects at single doses up to 238 mg and multiple doses up to 100 mg twice daily. There were no serious adverse events or adverse events leading to discontinuation. All reported adverse events were of mild to moderate intensity. No trends were seen in bile acids, triglycerides, or glucose levels, and plasma levels of 4β-OH-cholesterol (a CYP3A4 biomarker) were unchanged after treatment, suggesting low risk for CYP3A4-mediated drug-drug interactions [2].
Comprehensive toxicological data for AZD0284 are not extensively documented in publicly available sources. As a research-grade compound, AZD0284 is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. Comprehensive toxicological profiling (e.g., LD50, maximum tolerated dose, organ-specific toxicity) is not available from the current search results and would require consultation of the primary literature or safety data sheets. |
| References |
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| Additional Infomation |
AZD0284 is an inverse agonist of the nuclear receptor RORγ (retinoic acid-related orphan receptor γ) being developed for the treatment of Th17-driven autoimmune diseases such as psoriasis [1, 2].
The compound has low solubility and moderate permeability; a solution containing Captisol was used to enhance solubility and exposure in clinical studies [2]. Key drivers for compound design included potency in human Th17 cell assay, reduction of lipophilicity, and structure-based drug design (SBD) to target polar interactions in the hydrophobic RORγ LBD [1]. Clinical trials completed include: NCT02976831 (first-in-human SAD/MAD in healthy subjects) [2]. AZD0284 is a research compound developed for studying the role of RORγ in TH17 cell differentiation and inflammatory diseases. The compound is a selective inverse agonist of RORγ with a pIC50 of 7.4 and selectivity over RORα and RORβ up to 5 μM. AZD0284 inhibits IL-17A production in human TH17 cells and reduces the polarization of TH17 cells into pathogenic TH17/1 cells. The compound has the potential for the treatment of plaque-type psoriasis vulgaris and respiratory diseases. AZD0284 is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical inflammatory disease research. AZD0284 is available from various chemical suppliers for research purposes. |
| Molecular Formula |
C21H18F6N2O5S
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|---|---|
| Molecular Weight |
524.433445453644
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| Exact Mass |
524.084
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| Elemental Analysis |
C, 48.10; H, 3.46; F, 21.74; N, 5.34; O, 15.25; S, 6.11
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| CAS # |
2101291-07-8
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| PubChem CID |
129205086
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| Appearance |
White to off-white solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
35
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| Complexity |
910
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C)(C1C=CC2=C(C=1)CN(C(C)=O)[C@H]2C(NC1C=CC(=CC=1)C(C(F)(F)F)(C(F)(F)F)O)=O)(=O)=O
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| InChi Key |
QYYZXEPEVBXNNA-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C21H18F6N2O5S/c1-11(30)29-10-12-9-15(35(2,33)34)7-8-16(12)17(29)18(31)28-14-5-3-13(4-6-14)19(32,20(22,23)24)21(25,26)27/h3-9,17,32H,10H2,1-2H3,(H,28,31)/t17-/m1/s1
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| Chemical Name |
(R)-2-acetyl-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-(methylsulfonyl)isoindoline-1-carboxamide
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| Synonyms |
AZD-0284; AZD 0284; 2101291-07-8; 5G4XF6VU2Y; RefChem:115982; AZD0284.
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), 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)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~190.68 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.58 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (1.58 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 8.3 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: ≥ 0.83 mg/mL (1.58 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 | 1.9068 mL | 9.5342 mL | 19.0683 mL | |
| 5 mM | 0.3814 mL | 1.9068 mL | 3.8137 mL | |
| 10 mM | 0.1907 mL | 0.9534 mL | 1.9068 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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