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Purity: ≥98%
AZD9567 is a novel, potent, oral bioactive, non-steroidal and selective glucocorticoid receptor modulator (SGRM) with an IC50 of 3.8 nM. AZD9567 has excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. AZD9567 exhibits excellent efficacy in the streptococcal cell wall (SCW) reactivation model of joint inflammation. It is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.
| ln Vitro |
AZD9567 exhibits a partial agonist profile in transactivation (TA) reporter gene assays. In the TA agonist (TAag) mode using ChaGoK1 cells, it has an EC50 of 11 nM with 36% efficacy. In the TA antagonist (TAantag) mode, it inhibits dexamethasone-induced transactivation with an IC50 of 160 nM and 56% efficacy.[1]
AZD9567 is a full agonist in transrepression (TR) reporter gene assays. It inhibits PMA-stimulated AP-1 signaling in ChaGoK1 cells with an IC50 of 7.0 nM and 87% efficacy.[1] In human whole blood, AZD9567 inhibits LPS-induced TNFα release with an unbound plasma IC50u of 0.18 nM and 75% efficacy.[1] In primary human hepatocytes, AZD9567 does not induce the expression of tyrosine aminotransferase (TAT) mRNA, a marker for hyperglycemic effects, up to 1 μM. However, it can dose-dependently inhibit the TAT induction caused by prednisolone, confirming target engagement.[1] In human fetal osteoblasts (hFOB), AZD9567 shows no significant effect on the mRNA expression of osteoprotegerin (OPG), a marker for bone resorption, up to 1 μM.[1] AZD9567 demonstrates high selectivity for GR over other nuclear hormone receptors. Its binding IC50 is >38 μM for the mineralocorticoid receptor (MR), >100 μM for the androgen receptor (AR) and estrogen receptors (ERα, ERβ), and 5.3 μM for the progesterone receptor (PR).[1] In a nuclear translocation assay, AZD9567 induces full translocation of GR into the nucleus but does not cause translocation of MR even at high concentrations.[1] In surface plasmon resonance (SPR) assays, the GR ligand-binding domain (LBD) complex with AZD9567 recruits a panel of five coregulator peptides (NCOA2, NR0B1, NRIP1, PRGC1, PRGC2) with an intermediate binding response, between the strong recruitment by the prednisolone complex and the weak recruitment by the antagonist (mifepristone) complex.[1] AZD9567 showed excellent selectivity in a panel of over 300 in vitro binding and enzyme assays, including 125 kinases and cardiovascular ion channels, with no significant off-target activity.[1] |
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| ln Vivo |
In a rat model of joint inflammation, mizakola treatment (15 mg/kg/day, orally delivered daily for 8 days) demonstrated great in vivo efficacy [1].
In the rat streptococcal cell wall (SCW) reactivation model of joint inflammation, oral administration of AZD9567 (0.1, 0.3, 1, and 3 mg/kg/day, QD for 8 days) dose-dependently inhibited ankle swelling. The efficacy was comparable to prednisolone at the tested doses.[1] |
| Enzyme Assay |
The affinity of compounds for the human glucocorticoid receptor (GR) was determined in a fluoroligand binding assay using the fluorescent polarization method with partially purified human full-length GR.[1]
The affinity for the human mineralocorticoid receptor (MR) ligand-binding domain was determined in a scintillation proximity assay (SPA).[1] The affinity for the agonist site of human estrogen receptors (ERα and ERβ) expressed in transfected cells was determined in a fluoroligand binding assay using the fluorescence polarization method.[1] |
| Cell Assay |
The transactivation (TA) assay in agonist mode (TAag) was performed in ChaGoK1 cells stably transfected with a GRE-LacZ construct (MMTV-LacZ). Cells were plated, incubated for 24 hours, then treated with compounds for another 24 hours. β-Galactosidase activity was measured using ONPG substrate, and absorbance was read at 420 nm. EC50 values were calculated from concentration-response curves.[1]
The transactivation assay in antagonist mode (TAantag) was performed similarly, except dexamethasone was added 4-5 hours prior to compound addition to induce the response. The inhibition of this dexamethasone-induced activity was measured.[1] The transrepression (TR) assay was performed in ChaGoK1 cells stably transfected with a TRE-LacZ construct. Cells were stimulated with PMA, then compounds were added 4-5 hours later. After 24 hours, β-galactosidase activity was measured using MUG substrate, and fluorescence was detected.[1] The inhibition of LPS-induced TNFα release in human whole blood was assessed. Heparinized blood was preincubated with compounds for 45 minutes, then stimulated with LPS for 18 hours. Plasma TNFα levels were quantified using an AlphaLISA assay.[1] The rat whole blood assay was performed similarly, using pooled rat blood stimulated with LPS, and TNFα was measured by ELISA.[1] The effect on TAT mRNA expression was evaluated in cryopreserved primary human hepatocytes. Cells were plated, then treated with compounds for 18 hours. Total RNA was isolated, cDNA synthesized, and TAT mRNA levels were quantified by RT-qPCR using TaqMan probes, normalized to HPRT1.[1] The effect on OPG mRNA expression was evaluated in human fetal osteoblasts (hFOB). Differentiated cells were treated with compounds for 4 hours. Total RNA was isolated, and OPG mRNA levels were quantified by RT-qPCR using TaqMan probes, normalized to HPRT1.[1] Nuclear translocation of GR and MR was studied using imaging techniques. Cells were treated with compounds, and the percentage of receptor localized in the nucleus relative to total cellular levels was determined.[1] |
| Animal Protocol |
Animal/Disease Models: Female Lewis rats (175-200 g) antigen-induced joint inflammation model, sensitized by intra-articular injection of 5 μg SCW [1].
Doses: 15 mg/kg/day. Route of Administration: Daily oral administration for 8 days. Experimental Results: Inhibition of ankle joint swelling in rat SCW model. For the in vivo efficacy study in the rat SCW model, female Lewis rats (175-200 g) were used. Monocarticular joint inflammation was induced by intra-articular sensitization with SCW extract, followed 21 days later by systemic intravenous challenge. Compounds (AZD9567 or prednisolone) or vehicle (0.5% HPMC/0.1% Tween 80 in water) were administered orally once daily (QD) for 8 days, starting one day before the challenge. Ankle width was measured daily, and the area under the curve (AUC) of ankle swelling over 6 days post-challenge was calculated to assess efficacy.[1] For pharmacokinetic studies in rats, AZD9567 was administered intravenously as a solution at 0.8 mg/kg and orally as a crystalline suspension in 0.5% HPMC at 2.1 mg/kg. Blood samples were collected at various time points for plasma concentration analysis.[1] |
| ADME/Pharmacokinetics |
In male Han-Wistar rats, after a single oral administration of 2.1 mg/kg (crystal suspension), the Tmax of AZD9567 was 2.0 h, the Cmax (dose normalized to 1 mg/kg) was 0.95 μM, and the AUC0-∞ (dose normalized) was 5.2 μM·h. The terminal half-life (T1/2) after oral administration was 1.9 h, and the terminal half-life after intravenous administration was 2.3 h. The oral bioavailability (F) was 52%, the systemic clearance (Cl) was 4.5 mL/min/kg, and the steady-state volume of distribution (Vss) was 0.66 L/kg. [1] In beagle dogs, after oral administration of 0.5 mg/kg of the crystalline substance, the bioavailability of AZD9567 was 48%, and the systemic clearance was 3.2 mL/min/kg. [1]
By scaling preclinical data, human pharmacokinetic characteristics were predicted. The estimated oral bioavailability was approximately 50%, with a low volume of distribution (0.3 L/kg), a total plasma clearance of 0.7 mL/min/kg, and a predicted terminal half-life of approximately 5 hours. [1] |
| Toxicity/Toxicokinetics |
Compared with prednisolone, AZD9567 showed significantly improved in vitro therapeutic index (TI) and therapeutic advantage (TA), particularly in hyperglycemic markers (induction of TAT in hepatocytes) and bone resorption markers (downregulation of OPG in osteoblasts), while its anti-inflammatory efficacy (inhibition of TNFα in whole blood) was relatively low. [1] At concentrations up to 1 μM, AZD9567 did not induce TAT or affect OPG expression in relevant human cell assays, while prednisolone showed significant effects on these adverse reaction markers. [1] AZD9567 exhibited selectivity of more than 1000-fold for cardiovascular ion channels and did not show significant activity in a series of off-target assays. [1]
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| References | |
| Additional Infomation |
AZD9567 is a novel oral nonsteroidal glucocorticoid receptor modulator (SGRM) whose mechanism of action is to separate the anti-inflammatory efficacy from the key metabolic and bone-related side effects associated with traditional glucocorticoids (such as prednisolone). [1]
The drug's design strategy is based on constructing a partial agonist in the transcriptional activation (TA) pathway (associated with side effects) while maintaining its full agonist role in the transcriptional repression (TR) pathway (associated with anti-inflammatory efficacy). [1] This compound is derived from the structural optimization of the phenylindazole nonsteroidal glucocorticoid receptor (GR) modulator backbone, introducing an N-methylpyridinone group to interact with the helix 3-5 interface, and introducing an isopropyl group to regulate the AF-2 surface near helix 12, thereby endowing it with partial agonist properties. [1] The co-crystal structure of GR LBD and AZD9567 confirms the interaction between the two. [1] AZD9567 is currently undergoing clinical trials to compare its efficacy and side effects with those of prednisolone. [1] |
| Molecular Formula |
C27H28F2N4O3
|
|---|---|
| Molecular Weight |
494.533033370972
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| Exact Mass |
494.212
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| CAS # |
1893415-00-3
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| PubChem CID |
121248172
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| Appearance |
Off-white to light brown solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
36
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| Complexity |
871
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC(C)(C(N[C@@H]([C@H](C1C=CC=CC=1)OC1C=CC2=C(C=NN2C2C=CC(N(C)C=2)=O)C=1)C(C)C)=O)F
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| InChi Key |
ZQFNDBISEYQVRR-LOSJGSFVSA-N
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| InChi Code |
InChI=1S/C27H28F2N4O3/c1-17(2)24(31-26(35)27(3,28)29)25(18-8-6-5-7-9-18)36-21-11-12-22-19(14-21)15-30-33(22)20-10-13-23(34)32(4)16-20/h5-17,24-25H,1-4H3,(H,31,35)/t24-,25+/m0/s1
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| Chemical Name |
2,2-difluoro-N-[(1R,2S)-3-methyl-1-[1-(1-methyl-6-oxopyridin-3-yl)indazol-5-yl]oxy-1-phenylbutan-2-yl]propanamide
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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 : ~100 mg/mL (~202.21 mM)
H2O : ~0.67 mg/mL (~1.35 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.06 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 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 (5.06 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 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 (5.06 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 | 2.0221 mL | 10.1106 mL | 20.2212 mL | |
| 5 mM | 0.4044 mL | 2.0221 mL | 4.0442 mL | |
| 10 mM | 0.2022 mL | 1.0111 mL | 2.0221 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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