| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 100mg |
|
||
| 500mg | |||
| 1g |
Purity: ≥98%
| Targets |
Mineralocorticoid receptor (MR)
|
|---|---|
| ln Vitro |
The effects of eplerenone and balcinrenone (AZD9977) on MR, GR, PR, and AR in binding tests. For MR, GR, and PR, the observed pKi were 7.5, 5.4, and 4.6, respectively. Using a reporter test in which full-length MR drives a luciferase reporter gene in U2-OS cells, the functional relationship between balcinrenone and MR was investigated. MR triggered by aldosterone is inhibited by balcinrenone, with an IC50 of 0.28 μM. Balcinrenone in this experiment reduced only 69% of MR activity, despite eplerenone being a complete antagonist. MR LBDs from humans, mice, or rats were used in reporter gene assays to assess the species-selective efficacy of balcinrenone. The IC50 values that correspond to these are 0.37μM, 0.08μM, and 0.08μM, in that order.
AZD9977 shows potent binding to MR with a pKi of 7.5 in binding tests. It demonstrates selectivity over GR (pKi=5.4) and PR (pKi=4.6). In a reporter assay using full-length MR driving a luciferase reporter gene in U2-OS cells, aldosterone-triggered MR activity is inhibited by AZD9977 with an IC50 of 0.28 μM. AZD9977 in this experiment reduced only 69% of MR activity, whereas eplerenone is a complete antagonist. Species-selective efficacy is observed with IC50 values of 0.37 μM (human), 0.08 μM (mouse), and 0.08 μM (rat) MR LBDs. |
| ln Vivo |
In uninephrectomized male Sprague Dawley rats given aldosterone and fed a high-salt diet, balcinrenone (AZD9977) (oral; 10-100 mg/kg; 4 weeks) dose-dependently lowers UACR compared to vehicle. Balcinrenone is just as effective in protecting the kidneys as a complete MR antagonist, despite the observation of partial antagonism in in vitro tests [1]. In comparison to vehicle treatment, oral balcinrenone (100 mg/kg) coadministered with enalapril avoided further progression of the disease and decreased urine albumin excretion (UAE). Even though the reduction in UAE was not statistically significant, coadministration of enalapril had a definite additive effect [1].
In uninephrectomized male Sprague Dawley rats given aldosterone and fed a high-salt diet, AZD9977 (oral; 10-100 mg/kg; 4 weeks) dose-dependently lowers UACR compared to vehicle. AZD9977 is just as effective in protecting the kidneys as a complete MR antagonist, despite the observation of partial antagonism in in vitro tests. In comparison to vehicle treatment, oral AZD9977 (100 mg/kg) coadministered with enalapril prevented further progression of the disease and decreased urine albumin excretion. Coadministration of enalapril has an additive effect on renal protection. |
| Enzyme Assay |
Binding affinity is assessed using radioligand binding assays against MR, GR, PR, and AR to determine pKi values. Functional activity is evaluated using a reporter gene assay in U2-OS cells expressing full-length MR and a luciferase reporter gene, with aldosterone-stimulated activity measured to determine IC50 values. Species-selective efficacy is assessed using MR LBDs from human, mouse, or rat.
|
| Cell Assay |
Cellular potency is evaluated in U2-OS cells expressing full-length MR with a luciferase reporter gene. Aldosterone-triggered MR activity is measured in the presence of AZD9977 to determine IC50 values. Species differences in MR modulation are assessed using MR ligand-binding domains from human, mouse, or rat in reporter gene assays.
|
| Animal Protocol |
Animal/Disease Models: Uninephrectomized male Sprague Dawley rats were given aldosterone and fed a high-salt diet AZD9977 [1]
Doses: 10, 30 and 100 mg/kg Route of Administration: po (po (oral gavage)) 10-100 mg/kg; 4 weeks Experimental Results: Improved renal function and histology in animal models of CKD. Animal/Disease Models: 8weeks old uninephrectomized Db/db mice, treated from 18 weeks to 22 weeks of age [1] Doses: 100 mg/kg Route of Administration: oral; Route of Administration: oral. 100 mg/kg; co-administration with enalapril results in: reduction of proteinuria in patients with diabetic nephropathy. Coadministration of enalapril and AZD9977 has an additive effect on renal pathology scores. In vivo efficacy is evaluated in uninephrectomized male Sprague Dawley rats given aldosterone and fed a high-salt diet. AZD9977 is administered orally at 10, 30, and 100 mg/kg for 4 weeks. Urinary albumin-to-creatinine ratio (UACR) is measured to assess renal function. Additional studies are conducted in 8-week-old uninephrectomized db/db mice treated from 18 to 22 weeks of age with AZD9977 at 100 mg/kg, alone or coadministered with enalapril. |
| ADME/Pharmacokinetics |
AZD9977 is rapidly absorbed after oral administration, with dose-proportional systemic exposure up to 200 mg and a short plasma half-life (t1/2) of 2-3 hours. The median time of maximum concentration is 0.50-0.84 hours across dose groups. Area under the curve and maximum concentration are approximately dose proportional, but elimination and accumulation terminal half-life increased with dose. Oral bioavailability is approximately 82%, and in vitro metabolism studies have shown that cytochrome P450 (CYP) enzymes are involved in the metabolism of AZD9977.
|
| Toxicity/Toxicokinetics |
AZD9977 has been evaluated in Phase 1 clinical trials for safety, tolerability, and pharmacokinetics in healthy volunteers. The compound shows favorable safety and tolerability profiles at studied doses. Studies have also been conducted to assess the effect of severe renal impairment on the pharmacokinetics, safety, and tolerability of balcinrenone. AZD9977 is generally well-tolerated in clinical studies.
|
| References | |
| Additional Infomation |
AZD-9977 is being investigated in clinical trial NCT03843060 (a phase 1 study designed to evaluate the pharmacokinetics of AZD9977 alone and in combination with itraconazole in healthy volunteers).
AZD9977 (Balcinrenone) is a novel MR modulator being developed for heart failure and chronic kidney disease. It represents a unique approach to MR modulation, functioning as a partial antagonist rather than a full antagonist like eplerenone or spironolactone. This mechanism offers the potential for organ protection with reduced urinary electrolyte effects. The compound has been studied in multiple Phase 1 clinical trials in healthy volunteers and patients with renal impairment. |
| Molecular Formula |
C20H18FN3O5
|
|---|---|
| Molecular Weight |
399.372428417206
|
| Exact Mass |
399.123
|
| CAS # |
1850385-64-6
|
| PubChem CID |
118599727
|
| Appearance |
White to off-white solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Boiling Point |
731.4±60.0 °C at 760 mmHg
|
| Flash Point |
396.1±32.9 °C
|
| Vapour Pressure |
0.0±2.4 mmHg at 25°C
|
| Index of Refraction |
1.597
|
| LogP |
1.1
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
29
|
| Complexity |
662
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CNC(=O)C[C@H]1COC2=C(N1C(=O)C3=CC4=C(C=C3)OCC(=O)N4)C=CC(=C2)F
|
| InChi Key |
MBKYLPOPYYLTNW-ZDUSSCGKSA-N
|
| InChi Code |
InChI=1S/C20H18FN3O5/c1-22-18(25)8-13-9-28-17-7-12(21)3-4-15(17)24(13)20(27)11-2-5-16-14(6-11)23-19(26)10-29-16/h2-7,13H,8-10H2,1H3,(H,22,25)(H,23,26)/t13-/m0/s1
|
| Chemical Name |
2-[(3S)-7-Fluoro-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]-N-methylacetamide
|
| Synonyms |
AZD9977 AZD-9977 AZD 9977
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~625.99 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.21 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 20.8 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: ≥ 2.08 mg/mL (5.21 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 20.8 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: ≥ 2.08 mg/mL (5.21 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 | 2.5039 mL | 12.5197 mL | 25.0394 mL | |
| 5 mM | 0.5008 mL | 2.5039 mL | 5.0079 mL | |
| 10 mM | 0.2504 mL | 1.2520 mL | 2.5039 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA