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| Targets |
Glucocorticoid receptor (corticosteroid receptor); no IC50, Ki, EC50, or DC50 values are reported in the provided study. The study references an ex vivo binding assay (Luzzani et al., 1983) showing a binding ratio of 28.5:1 for hydroxycortisone to deflazacort in rat thymus, but this is not original data from this paper.
21-Deacetyldeflazacort targets the glucocorticoid receptor (GR). As an active glucocorticoid, it binds to the GR and modulates gene expression, leading to anti-inflammatory and immunosuppressive effects. The compound inhibits 48-hour homologous passive cutaneous anaphylaxis in rats. It has benefits in certain muscular dystrophies. Its mechanism of action involves transactivation of anti-inflammatory genes and transrepression of pro-inflammatory genes. |
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| ln Vitro |
In vitro, 21-deacetyldeflazacort exhibits anti-inflammatory and immunosuppressive activities. As the active metabolite of deflazacort, it is responsible for the therapeutic effects of the prodrug. The compound has been studied for its effects on various inflammatory and immune responses. Its glucocorticoid activity is mediated through GR activation. Detailed in vitro potency data are limited.
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| ln Vivo |
In the rat model, 21-deacetyldeflazacort (administered as the prodrug deflazacort at 0.15 mg/day, s.c., for 8 days) resulted in a daily weight gain of 3.6 ± 0.3 g/day, which was significantly higher than the cortisone-treated group (1.2 ± 0.4 g/day, p<0.05) but lower than controls (7.7 ± 0.5 g/day). Final body weight at day 44 was 177 ± 4.5 g for DF1 vs 158 ± 5.9 g for cortisone (p<0.05). Nose-tailtip length was 32.9 ± 0.2 cm for DF1 vs 32.1 ± 0.3 cm for cortisone (p<0.03); both were shorter than controls (34.1 ± 0.3 cm, p<0.005). Thymus weight (corrected per 100g body weight) was reduced comparably in DF1 (corticosterone-equivalent dose) and cortisone groups (no significant difference between DF1 and cortisone), indicating bio-equivalence at the doses used. Food efficiency (g weight gain/g food intake) was 0.22 ± 0.01 for DF1, significantly greater than cortisone (0.18 ± 0.01, p=0.023), but still lower than controls (0.25 ± 0.01). Hepatic IGF-I mRNA was reduced to 75% of control in DF1 (not significantly different from control), whereas cortisone reduced it to 59% (p<0.05 vs control). Hepatic GHR mRNA was 95% of control in DF1 (not significant), while cortisone reduced it to 52% (p<0.05 vs control and vs DF1). No glycosuria was observed in DF1-treated rats, whereas 3/8 cortisone-treated rats developed mild glycosuria. Serum glucose in DF1 was 8.8 ± 3.2 mmol/L vs 14.6 ± 6.4 mmol/L in cortisone. [1]
In vivo, 21-deacetyldeflazacort inhibits 48-hour homologous passive cutaneous anaphylaxis in rats. However, it has no significant effects on active systemic anaphylaxis in mice, on the Schultz-Dale reaction in the isolated guinea-pig trachea, or on compound 48/80-induced reactions or the Arthus reaction in mice. As the active metabolite of deflazacort, it contributes to the anti-inflammatory and immunosuppressive effects of the prodrug. The compound has benefits in certain muscular dystrophies. |
| Enzyme Assay |
No enzyme assays (e.g., receptor binding, enzymatic activity) are described in the provided study. The study mentions ex vivo binding data from other publications but does not provide original experimental protocols for enzyme or receptor binding assays.
General protocols for glucocorticoid receptor binding assays use cytosolic preparations from rat liver or recombinant GR. Cytosol is incubated with [3H]dexamethasone and varying concentrations of 21-deacetyldeflazacort in binding buffer at 4°C for 16-24 hours. Bound ligand is separated using dextran-coated charcoal. Radioactivity is counted, and IC50 values are calculated. Nonspecific binding is determined using 100-fold excess unlabeled dexamethasone. Specific binding is calculated by subtracting nonspecific binding from total binding. |
| Cell Assay |
General protocols for glucocorticoid activity in cell-based systems use reporter gene assays. Cells transfected with GRE-luciferase reporter and GR expression vector are treated with various concentrations of 21-deacetyldeflazacort for 24 hours. Luciferase activity is measured, and EC50 values are calculated. Alternatively, cytokine production assays use LPS-stimulated macrophages or PBMCs treated with the compound for 24 hours, followed by ELISA measurement of TNF-α, IL-6, and IL-1β in culture supernatants. The percentage inhibition of cytokine production is calculated.
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| Animal Protocol |
The animal experiment used 23-day-old male Long Evans rats. After a 7-day control period, treatment was started at 37 days of age and continued for 8 consecutive days. Rats received daily subcutaneous injections in the scapular region at 10:00 h of either vehicle (0.9% ethanol in saline), cortisone acetate (5.0 mg/day), deflazacort 0.15 mg/day (DF1), or deflazacort 0.075 mg/day (DF2). Deflazacort powder was dissolved in ethanol and diluted with isotonic saline to a final 0.9% ethanol solution. All animals were housed in metabolic cages with ad libitum access to standard powdered chow and water. Daily body weight and food intake were measured. Urine was collected for 24 h on days 33, 38, and 43 for calcium excretion measurement. On day 45, animals were anesthetized with pentobarbital (50 mg/kg), nose-tailtip length was measured, and blood and organs (liver, thymus) were harvested for mRNA analysis and thymus weight determination. Hepatic IGF-I and GHR mRNA were measured by RNAase protection assay using radiolabeled antisense probes; total RNA was extracted by guanidine thiocyanate-cesium chloride ultracentrifugation, and protected fragments were separated on denaturing polyacrylamide gels and quantified by densitometry. GAPDH was used as an internal standard. [1]
General protocols for in vivo anti-inflammatory activity use the passive cutaneous anaphylaxis model in rats. Rats are sensitized with IgE antibodies intradermally. 24-48 hours later, the antigen is injected intravenously with Evans blue dye. 21-Deacetyldeflazacort is administered orally or intraperitoneally at doses of 1-10 mg/kg before antigen challenge. The area of blue dye extravasation is measured as an indicator of vascular permeability and mast cell degranulation. The percentage inhibition of the reaction is calculated compared to vehicle-treated controls. Dexamethasone serves as a positive control. |
| ADME/Pharmacokinetics |
The study provides pharmacokinetic data for deflazacort (the prodrug of 21-deacetyldeflazacort) from previous publications: In rats, deflazacort has a plasma half-life of 1.13 h for the α-phase and 11.56 h for the β-phase. Deflazacort is metabolized in the liver to at least five different metabolites; the oxazoline group is not known to undergo degradation or metabolism in any species. No direct pharmacokinetic parameters (absorption, distribution, excretion, oral bioavailability) for 21-deacetyldeflazacort itself are reported in the present study. [1]
21-Deacetyldeflazacort is the active metabolite of the prodrug deflazacort. Following oral administration of deflazacort, the prodrug is rapidly converted by esterases to 21-deacetyldeflazacort. The active metabolite has a molecular weight of 399.5 g/mol (C23H29NO5). It is distributed to various tissues, including inflamed tissues, where it exerts its anti-inflammatory effects. The compound is metabolized in the liver and excreted via the kidneys. |
| Toxicity/Toxicokinetics |
In this study, 21-deacetyldeflazacort (administered as deflazacort 0.15 mg/day) did not induce hyperglycemia or glycosuria in rats, whereas cortisone (5.0 mg/day) caused mild glycosuria in 3 out of 8 animals, with elevated serum glucose (14.6 ± 6.4 mmol/L vs 8.8 ± 3.2 mmol/L in DF1). No ketonuria was observed. Thymus weight reduction was comparable between DF1 and cortisone, indicating significant immunosuppressive/lympholytic activity at the bio-equivalent dose. No other toxicity parameters (e.g., hepatic, renal) are reported. [1]
21-Deacetyldeflazacort has a toxicity profile consistent with other glucocorticoids. Long-term use can lead to adrenal suppression, Cushing's syndrome, osteoporosis, hyperglycemia, immunosuppression, and increased infection risk. The compound should be used with caution in patients with diabetes, hypertension, osteoporosis, or infections. Dose tapering is required to avoid adrenal crisis upon discontinuation. The safety profile of deflazacort (and its active metabolite) has been established in clinical use. |
| References |
Neuropharmacology.2012 Jun;62(7):2261-6;Eur J Endocrinol.1994 Dec;131(6):652-7.
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| Additional Infomation |
21-deacetyldeflazacort is the active metabolite of deflazacort, an oxazoline derivative of cortisone developed to reduce corticosteroid side effects. In this rat study, deflazacort (0.15 mg/day, s.c.) showed bio-equivalence to cortisone (5.0 mg/day) based on thymus weight reduction (thymolytic activity), confirming a dose equivalence ratio of 1:33 (deflazacort:cortisone) in rats, consistent with previous ex vivo receptor binding data. Despite equivalent immunosuppressive activity, deflazacort caused significantly less growth suppression (weight gain and length) than cortisone, and this correlated with preservation of hepatic GHR mRNA (95% of control vs 52% for cortisone) and less reduction in IGF-I mRNA. The study suggests that the growth-sparing effect of deflazacort may be mediated through less suppression of GHR and IGF-I gene expression, though direct effects on cartilage cannot be excluded. Deflazacort also showed a better metabolic profile with no glycosuria, contrasting with cortisone-induced mild hyperglycemia. The authors note that rats are approximately 10 times more sensitive to deflazacort than humans, so dose extrapolation to humans requires caution. Clinical studies cited show deflazacort is associated with less growth retardation in children compared to other corticosteroids. No FDA warnings are mentioned. [1]
21-Deacetyldeflazacort (21-desDFZ) is the active metabolite of the prodrug deflazacort. Deflazacort is an anti-inflammatory and immunosuppressive corticosteroid that is approved for the treatment of various inflammatory and autoimmune conditions, including Duchenne muscular dystrophy, rheumatoid arthritis, asthma, and inflammatory bowel disease. The prodrug is rapidly converted by esterases to the active metabolite 21-deacetyldeflazacort after oral administration. Deflazacort is approved by the FDA and other regulatory agencies for specific indications. |
| Molecular Formula |
C23H29NO5
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|---|---|
| Molecular Weight |
399.48006
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| Exact Mass |
399.204
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| CAS # |
13649-57-5
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| Related CAS # |
21-Desacetyldeflazacort-d5
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| PubChem CID |
3081431
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
585.0±50.0 °C at 760 mmHg
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| Melting Point |
228-230 °C
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| Flash Point |
307.6±30.1 °C
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| Vapour Pressure |
0.0±3.7 mmHg at 25°C
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| Index of Refraction |
1.690
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| LogP |
0.9
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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 |
2
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| Heavy Atom Count |
29
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| Complexity |
890
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| Defined Atom Stereocenter Count |
8
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| SMILES |
CC1=N[C@@]2([C@H](O1)C[C@@H]3[C@@]2(C[C@@H]([C@H]4[C@H]3CCC5=CC(=O)C=C[C@]45C)O)C)C(=O)CO
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| InChi Key |
KENSGCYKTRNIST-RVUAFKSESA-N
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| InChi Code |
InChI=1S/C23H29NO5/c1-12-24-23(18(28)11-25)19(29-12)9-16-15-5-4-13-8-14(26)6-7-21(13,2)20(15)17(27)10-22(16,23)3/h6-8,15-17,19-20,25,27H,4-5,9-11H2,1-3H3/t15-,16-,17-,19+,20+,21-,22-,23+/m0/s1
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| Chemical Name |
(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-8-(2-hydroxyacetyl)-6,9,13-trimethyl-5-oxa-7-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-6,14,17-trien-16-one
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.5033 mL | 12.5163 mL | 25.0325 mL | |
| 5 mM | 0.5007 mL | 2.5033 mL | 5.0065 mL | |
| 10 mM | 0.2503 mL | 1.2516 mL | 2.5033 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03783923 | TERMINATEDWITH RESULTS | Drug: Deflazacort | Limb-Girdle Muscular Dystrophy | PTC Therapeutics | 2019-10-31 | Phase 3 |
| NCT00759876 | TERMINATEDWITH RESULTS | Drug: Ataluren | Duchenne Muscular Dystrophy | PTC Therapeutics | 2008-08-13 | Phase 2 |
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