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Purity: ≥98%
AZD-0284 is a novel, potent, selective, inverse agonist of the nuclear receptor RORγ. It is in development for the treatment of plaque psoriasis vulgaris and respiratory tract disorders.
| 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]. |
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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]. |
| 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mouse model of skin inflammation, AZD0284 significantly reduced the number of IL-17A producing cells in the ear (unpublished data) [2].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]. |
| 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]. |
| 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].
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| 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]. |
| 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].
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| 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]. |
| 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
|
| Hydrogen Bond Acceptor Count |
11
|
| 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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