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Purity: ≥98%
AZD7594 (also known as AZ13189620) is a novel, potent selective nonsteroidal indazole ether-based glucocorticoid receptor modulators (SGRMs) with an IC50 of 0.9 nM. AZD-7594 is an inhaled selective glucocorticoid receptor (GCCR) modulator for the inhaled treatment of respiratory diseases. AZD7594 demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment. AZD-7594 is currently in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma. It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).
| Targets |
At an IC50 of 0.9 nM, AZD7594 is a very effective and specific modulator of the non-steroidal glucocorticoid receptor. Progesterone receptors, androgen receptors, mineralocorticoid receptors, ERα, and ERβ are unaffected by AZD7594 (IC50, >10 μM).
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| ln Vitro |
At an IC50 of 0.9 nM, AZD7594 is a very effective and specific modulator of the non-steroidal glucocorticoid receptor. Progesterone receptors, androgen receptors, mineralocorticoid receptors, ERα, and ERβ are unaffected by AZD7594 (IC50, >10 μM).
AZD7594 exhibited picomolar potency in cellular transrepression assay (Cell TR IC₅₀ = 0.056 ± 0.021 nM, n=4) with 107% efficacy relative to dexamethasone. In human peripheral blood mononuclear cells (PBMCs), it inhibited LPS-stimulated TNF-α release with IC₅₀ = 0.43 ± 0.16 nM (n=6) and 75% efficacy. It showed high selectivity for GR over other steroid hormone receptors (PR, MR, AR, ERα, ERβ) with no binding detected up to 10 μM. Intrinsic clearance in human hepatocytes was 29 μL/min/10⁶ cells, corresponding to a predicted hepatic extraction ratio (E_H) of 0.8 (80% of liver blood flow) [1] |
| ln Vivo |
Rat pulmonary edema can be successfully inhibited by AZD7594, which also exhibits anti-inflammatory properties [1].
In a rat model of Sephadex-induced airway inflammation, inhaled AZD7594 (dry powder inhalation) potently inhibited lung edema with an ED₅₀ of 0.8 μg/kg (95% CI: 0.45–1.5 μg/kg). The systemic glucocorticoid effect, assessed as thymic involution (25% reduction in thymus weight), had an ED₂₅ of 40 μg/kg (95% CI: 17–92 μg/kg), resulting in a therapeutic ratio (ED₂₅/ED₅₀) of 50 (95% CI: 18–140). AZD7594 showed prolonged inhibition of lung edema when pre-dosed 9 h (full inhibition) and 24 h (76% inhibition) prior to challenge, indicating potential for once-daily dosing. It demonstrated superior duration of effect compared to fluticasone propionate (3) in the same model [1] |
| Enzyme Assay |
GR binding affinity was determined using a fluorescence polarization assay or similar binding assay format. The assay measured displacement of a fluorescent ligand from the human GR ligand-binding domain. Values are reported as mean IC₅₀ ± SD from multiple replicates.
Selectivity against other steroid hormone receptors (PR, MR, AR, ERα, ERβ) was assessed in competitive binding assays, with no detectable binding up to 10 μM [1] |
| Cell Assay |
Cellular transrepression activity (Cell TR) was assessed using a reporter gene assay measuring inhibition of AP-1 mediated transcription in a GR-expressing cell line. Cells were treated with compound and stimulated with an AP-1 inducer, followed by luminescence readout.
Inhibition of TNF-α release in human PBMCs: freshly isolated PBMCs were pre-incubated with compound, then stimulated with LPS. TNF-α levels in supernatant were quantified by ELISA. Cellular potency and efficacy were calculated relative to dexamethasone (set as 100%) [1] |
| Animal Protocol |
Rat Sephadex-induced airway inflammation model: Male Han Wistar rats were challenged intratracheally with Sephadex particles to induce lung edema and inflammation.
AZD7594 was administered as a dry powder inhalation (DPI) using an aerosol delivery system that mimics active breathing. Doses were normalized to 0.1 μmol/kg lung dose. For efficacy assessment, animals received a single DPI administration of AZD7594 at various doses (0.6–47.9 μg/kg) prior to Sephadex challenge. Lung weight (edema) and thymus weight were measured 24 h post-challenge. For duration studies, compound was administered 9 h or 24 h before Sephadex challenge at a dose of 30 μg/kg (approx. 3× ED₉₀) [1] |
| ADME/Pharmacokinetics |
In rats after intravenous administration: plasma clearance (CL) = 30 mL/min/kg, steady-state volume of distribution (V_ss) = 0.16 L/kg, terminal half-life (t₁/₂) = 0.1 h, oral bioavailability (F) < 0.1%. In rats after inhalation of the dry powder: prolonged pulmonary retention time, mean residence time (MRT) = 23 h, apparent terminal half-life in the lungs = 17 h, with 73% of the dose remaining in the lungs 4 hours after administration. Thermodynamic solubility (HIF) in human intestinal fluid = 0.60 μM. AZD7594 was rapidly cleared from human hepatocytes (CL_int = 29 μL/min/10⁶ cells), with a high expected liver extraction rate (E_H = 0.8). Metabolites were identified in human hepatocytes, and rats and dogs exhibited multiple degradation pathways, including oxidation of the benzodioxane moiety and cleavage of the indazole ether pharmacophore, ultimately producing inactive metabolites [1].
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| Toxicity/Toxicokinetics |
Due to its high hepatic clearance and low oral bioavailability, the systemic exposure is low, suggesting a reduced risk of systemic glucocorticoid side effects.
This compound did not show binding to MR, PR, AR, ERα or ERβ at concentrations up to 10 μM, indicating that it has good steroid receptor selectivity[1]. |
| References | |
| Additional Infomation |
See also: Velsecorat (note moved to).
AZD7594 (also known as compound 15m) is a second-generation inhaled selective glucocorticoid receptor modulator (SGRM) derived from an indazole ether skeleton. It is designed for once-daily inhaled treatment of asthma and chronic obstructive pulmonary disease (COPD) with better lung targeting and lower systemic exposure compared to the first-generation candidate AZD5423 (1b) and the benchmark inhaled glucocorticoid fluticasone propionate. Its stereochemical configuration is (1R,2S,3′R); only the (1R,2S) configuration of the central 1-aryl-2-aminopropoxy moiety is essential for efficacy. It has shown dose-dependent efficacy in a phase II pulmonary function study in asthmatic patients (ClinicalTrials.gov registration number: NCT02479412) [1] |
| Molecular Formula |
C32H32F2N4O6
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| Molecular Weight |
606.616495132446
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| Exact Mass |
606.229
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| CAS # |
1196509-60-0
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| PubChem CID |
67041274
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
778.9±60.0 °C at 760 mmHg
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| Flash Point |
424.9±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.640
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| LogP |
3.44
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
44
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| Complexity |
1010
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@@H]([C@@H](C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)N[C@@H]6CCOC6)NC(=O)C(C)(F)F
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| InChi Key |
ZZWJKLGCDHYVMB-QMQODZDESA-N
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| InChi Code |
InChI=1S/C32H32F2N4O6/c1-19(36-31(40)32(2,33)34)29(20-6-9-27-28(16-20)43-13-12-42-27)44-25-7-8-26-22(15-25)17-35-38(26)24-5-3-4-21(14-24)30(39)37-23-10-11-41-18-23/h3-9,14-17,19,23,29H,10-13,18H2,1-2H3,(H,36,40)(H,37,39)/t19-,23?,29-/m0/s1
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| Chemical Name |
3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
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| Synonyms |
AZ13189620; AZ-13189620; AZ 13189620; AZD-7594; AZD 7594; AZD7594;
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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 : ≥ 83.3 mg/mL (~137.32 mM)
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| 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 | 1.6485 mL | 8.2424 mL | 16.4848 mL | |
| 5 mM | 0.3297 mL | 1.6485 mL | 3.2970 mL | |
| 10 mM | 0.1648 mL | 0.8242 mL | 1.6485 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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