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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.

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10mM (in 1mL DMSO)
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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


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


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


[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.


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]

[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

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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.


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