Home>>Signaling Pathways>> Metabolism>> Ferroptosis>>FG-4592 (ASP1517)

FG-4592 (ASP1517)

Catalog No.GC13139

FG-4592 (ASP1517) Chemical Structure

FG-4592, as an oral bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, can promote coordinated erythropoiesis through HIF-mediated transcription.

Size Price Stock Qty
10mM (in 1mL DMSO)
$36.00
In stock
10mg
$36.00
In stock
50mg
$103.00
In stock
100mg
$134.00
In stock
200mg
$206.00
In stock
500mg
$309.00
In stock

Customer Reviews

Based on customer reviews.

Tel: (626) 353-8530 Email: sales@glpbio.com

Sample solution is provided at 25 µL, 10mM.

Product Citations

Product Documents

Quality Control & SDS

View current batch:

Protocol

Cell experiment [1]:

Cell lines

Primary culture of hippocampal neurons

Preparation Method

Hippocampal primary neurons were treated with 50 μM and 10 μM FG-4592 for 72 h, starting from the second day in vitro. Microtubule-associated protein 2 (MAP2) staining and Western blotting were performed after cell collection.

Reaction Conditions

50 μM and 10 μM, 72h

Applications

FG-4592 promoted dendritic growth of primary hippocampal neurons in vitro.

Animal experiment [2]:

Animal models

Wild-type C57BL/6 mice (10–12 weeks old, weighing 25–28 g)

Preparation Method

The FG-4592 was dissolved in DMSO at the concentration of 50 mg/ml and further diluted in PBS to 1 mg/ml. The mice were pretreated with FG-4592 for 48 h in FG-4592+Doxorubicin group at a dose of 10 mg/kg/day before Doxorubicin treatment.

Dosage form

10 mg/kg/day;intraperitoneal injection

Applications

FG-4592 rescued the reduction of LVEF and LVFS induced by Doxorubicin. FG-4592 obviously attenuated Doxorubicin-induced acute cardiac dysfunction and cardiomyocyte injury.

References:

[1]. Li G, et al. FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats. Neurotherapeutics. 2020 Apr;17(2):664-675. 

[2]. Long G, et al. Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways. Front Pharmacol. 2020 Aug 5;11:1191.

Background

FG-4592, as an oral bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, can promote coordinated erythropoiesis through HIF-mediated transcription. FG-4592 was well tolerated and corrected anemia in incident HD and PD patients.[1]

In vitro, treated with 10 μM or 50 μM FG-4592 in Primary Hippocampal Neurons, FG-4592 dose-dependently increased protein levels of HIF-1, and its target genes EPO and VEGF, as well as BDNF and PSD95.[2] In vitro experiment it exhibited that treatment with 2, 10, and 20 μM FG-4592 dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway.[3] In HK-2 cells, treatment with 15 μM FG-4592 the injury induced by hypoxia remarkably ameliorated.[5]

In vivo experiment it shown that treatment with 20 mg/kg/day FG-4592 intraperitoneally in Rat significantly affected body weight gain. In vivo efficacy it indicated that the high dose FG-4592 (20 mg/kg/day) could effectively reverse CUMS-induced depression-like behaviors. [2] In vivo, mice were treated with 10 mg/kg FG-4592 intraperitoneally exhibited an improved renal function, compared with those without FG-4592 by biochemical and histological parameters.[4] In C57BL/6 mice, treatment with 25.0 mg/kg FG-4592 intraperitoneally 24 and 2 h before irradiation, and then followed by total body irradiation of 8.5 Gy or local abdominal irradiation of 25.0 Gy could dramatically improve the survival rate of mice after IR.[6]

References:
[1]Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, Chan DT, Leong R, et al. Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients. J Am Soc Nephrol. 2016 Apr;27(4):1225-33. 
[2]Li G, et al. FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats. Neurotherapeutics. 2020 Apr;17(2):664-675. 
[3]Yang DG, et al. Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway. Acta Pharmacol Sin. 2022 Aug 10. 
[4]Li X, et al. Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway. Oxid Med Cell Longev. 2020 Jan 20;2020:6286984.
[5]Miao AF, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation. Ren Fail. 2021 Dec;43(1):803-810.
[6]Feng Z, et al. FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway. Stem Cell Res Ther. 2022 Jun 21;13(1):271.

Chemical Properties

Cas No. 808118-40-3 SDF
Synonyms Roxadustat
Chemical Name 2-[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid
Canonical SMILES CC1=NC(=C(C2=C1C=C(C=C2)OC3=CC=CC=C3)O)C(=O)NCC(=O)O
Formula C19H16N2O5 M.Wt 352.34
Solubility ≥ 17.62 mg/mL in DMSO, ≥ 2.9 mg/mL in EtOH with ultrasonic and warming Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.

  • Molarity Calculator

  • Dilution Calculator

Mass
=
Concentration
x
Volume
x
MW*
 
 
 
**When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and MSDS / CoA (available online).

Calculate

Research Update

Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3 β/Nrf2 Pathway

Oxid Med Cell Longev2020 Jan 20;2020:6286984.PMID: 32051732DOI: 10.1155/2020/6286984

Folic acid- (FA-) induced kidney injury is characterized by the tubule damage due to the disturbance of the antioxidant system and subsequent interstitial fibrosis. FG-4592 is an inhibitor of prolyl hydroxylase of hypoxia-inducible factor (HIF), an antioxidant factor. The present study investigated the protective role of FG-4592 pretreatment at the early stage of the kidney injury and long-term impact on the progression of renal fibrosis. FG-4592 was administrated two days before FA injection in mice. On the second day after FA injection, the mice with FG-4592 pretreatment showed an improved renal function, compared with those without FG-4592 pretreatment, indicated by biochemical and histological parameters; meanwhile, the cellular content of iron, malondialdehyde, and 4-hydroxynonenal histologically decreased, implying the suppression of iron accumulation and lipid peroxidation. Simultaneously, upregulation of HIF-1α was found, along with Nrf2 activation, which was reflected by increased nuclear translocation and high-expression of downstream proteins, including heme-oxygenase1, glutathione peroxidase4, and cystine/glutamate transporter, as well as ferroportin. Correspondingly, the elevated levels of antioxidative enzymes and glutathione, as well as reduced iron accumulation, were observed, suggesting a lower risk of occurrence of ferroptosis with FG-4592 pretreatment. This was confirmed by reversed pathological parameters and improved renal function in FA-treated mice with the administration of ferrostatin-1, a specific ferroptosis inhibitor. Furthermore, a signal pathway study indicated that Nrf2 activation was associated with increased phosphorylation of Akt and GSK-3β, verified by the use of an inhibitor of the PI3K that phosphorylates Akt. Moreover, FG-4592 pretreatment also decreased macrophage infiltration and expression of inflammatory factors TNF-α and IL-1β. On the 14th day after FA injection, FG-4592 pretreatment decreased collagen deposition and expression of fibrosis biomarkers. These findings suggest that the protective role of FG-4592 pretreatment is achieved mainly by decreasing ferroptosis at the early stage of FA-induced kidney injury via Akt/GSK-3β-mediated Nrf2 activation, which retards the fibrosis progression.

Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients

J Am Soc Nephrol2016 Apr;27(4):1225-33.PMID: 26494833DOI: 10.1681/ASN.2015030241

Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb≤10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean±SD baseline Hb was 8.3±1.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by ≥2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean±SEM maximal change in Hb from baseline (ΔHb(max)), the primary endpoint, was 3.1±0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, ΔHb(max) was similar and larger than in the no-iron group. Hb response (increase in Hb of ≥1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation

Ren Fail2021 Dec;43(1):803-810.PMID: 33966598DOI: 10.1080/0886022X.2021.1915801

Hypoxia-induced inflammation is the critical pathological feature of acute kidney injury (AKI). Activation of hypoxia-inducible factor (HIF) signaling is considered as a central mechanism of body adapting to hypoxia. Hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 (Roxadustat) is a first-in-class HIF stabilizer for the treatment of patients with renal anemia. The current study aimed to investigate whether FG-4592 could protect against ischemia/reperfusion (I/R)-induced kidney injury via inhibiting inflammation. Here, efficacy of FG-4592 was evaluated in a mice model of I/R-induced AKI. Interestingly, improved renal function and renal tubular injuries, combined with reduced kidney injury molecule-1 were observed in the mice with FG-4592 administration. Meanwhile, inflammation responses in FG-4592-treated mice were also strikingly attenuated, as evidenced by the decreased infiltration of macrophages and neutrophils and down-regulated expression of inflammatory cytokines. In vitro, FG-4592 treatment significantly protected the tubular epithelial cells against hypoxia-induced injury, with suppressed inflammation and cell injuries. In summary, FG-4592 treatment could protect against the I/R-induced kidney injury possibly through diminishing tubular cells injuries and suppression of sequence inflammatory responses. Thus, our findings definitely offered a clinical potential approach in treating AKI.

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats

Neurotherapeutics2020 Apr;17(2):664-675.PMID: 31820273DOI: 10.1007/s13311-019-00807-3

Depression, plus the accompanying memory impairment, is one of the leading causes of disability worldwide. Thus, there is a critical need to develop new drugs based on distinct strategies. FG-4592, an inhibitor of prolyl hydroxylase, activates the hypoxia-inducible factor-1 (HIF-1) pathway, to produce multiple effects on cell properties. Here, we examined whether FG-4592 has antidepressant effects, using a chronic unpredictable mild stress (CUMS) procedure to establish rodent depression models. We found that FG-4592 not only reversed depressive behaviors but also improved CUMS-induced memory impairment. Mechanistically, FG-4592 could play an important role in promoting hippocampal neurogenesis and synaptic plasticity. At the molecular level, FG-4592 was found to activate HIF-1 and cAMP-responsive element-binding protein/brain-derived neurotrophic factor signaling pathways in vivo, as well as promote the expression of postsynaptic density (PSD) proteins, PSD95 and Homer1. An examination of primary hippocampal neurons showed that FG-4592 promoted dendritic growth. Taken together, our results not only provide an experimental basis for the future application of FG-4592 in clinical treatment of depression but also support the argument that the HIF-1 signaling pathway is a promising target for the treatment of depression.

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study

Am J Kidney Dis2016 Jun;67(6):912-24.PMID: 26846333DOI: 10.1053/j.ajkd.2015.12.020

Background: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin.
Study design: Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study.
Setting & participants: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa.
Intervention: Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited.
Outcomes: Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2).
Measurements: Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset).
Results: Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised.
Limitations: Short treatment duration and small sample size.
Conclusions: In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Reviews

Review for FG-4592 (ASP1517)

Average Rating: 5 ★★★★★ (Based on Reviews and 31 reference(s) in Google Scholar.)

5 Star
100%
4 Star
0%
3 Star
0%
2 Star
0%
1 Star
0%
Review for FG-4592 (ASP1517)

GLPBIO products are for RESEARCH USE ONLY. Please make sure your review or question is research based.

Required fields are marked with *

You may receive emails regarding this submission. Any emails will include the ability to opt-out of future communications.