Enarodustat (JTZ-951)
(Synonyms: JTZ-951) 目录号 : GC33634
A pan HIF-PH inhibitor
Cas No.:1262132-81-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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Enarodustat is a pan hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor (Kis = 16, 61, and 101 nM for HIF-PH1, -2, and -3, respectively).1 It increases erythropoietin (EPO) levels in Hep3B cells (EC50 = 4.7 ?M). Enarodustat (3 mg/kg) increases plasma EPO levels in control rats, as well as plasma EPO and hemoglobin levels in 5/6-nephrectomized rats. It also decreases renal fatty acid and amino acid metabolism and increases renal glucose metabolism in streptozotocin-induced rat and alloxan-induced mouse models of diabetic nephropathy.2
1.Fukui, K., Shinozaki, Y., Kobayashi, H., et al.JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factorEur. J. Pharmacol.859172532(2019) 2.Hasegawa, S., Tanaka, T., Saito, T., et al.The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney diseaseKidney Int.97(5)934-950(2020)
| Cas No. | 1262132-81-9 | SDF | |
| 别名 | JTZ-951 | ||
| Canonical SMILES | O=C(C(C1=NC=NN1C(CCC2=CC=CC=C2)=C3)=C3O)NCC(O)=O | ||
| 分子式 | C17H16N4O4 | 分子量 | 340.33 |
| 溶解度 | DMSO: 83.33 mg/mL (244.85 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9383 mL | 14.6916 mL | 29.3832 mL |
| 5 mM | 0.5877 mL | 2.9383 mL | 5.8766 mL |
| 10 mM | 0.2938 mL | 1.4692 mL | 2.9383 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
JTZ-951 (Enarodustat), a hypoxia-inducible factor prolyl hydroxylase inhibitor, improves iron utilization and anemia of inflammation: Comparative study against recombinant erythropoietin in rat
Eur J Pharmacol 2021 May 5;898:173990.PMID:33657422DOI:10.1016/j.ejphar.2021.173990.
Anemia with inflammation-induced defective iron utilization is a pathological condition observed in patients suffering from chronic kidney disease (CKD) or chronic inflammatory disease. There is no reasonable treatment for these conditions, because the effects of erythropoiesis stimulating agents (ESAs) or iron supplementation in the treatment of anemia are insufficient. JTZ-951 (Enarodustat) has been characterized as a novel, orally bioavailable inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), and has been developed as a novel therapeutic agent for anemia with CKD. In this study, the effects of JTZ-951 on iron utilization during erythropoiesis and on anemia of inflammation were compared with those of recombinant human erythropoietin (rHuEPO) using normal rat and rat model of anemia of inflammation. In normal rats, under conditions in which JTZ-951 and rHuEPO showed similar erythropoietic effect, repeated doses of JTZ-951 induced erythropoiesis while retaining the hemoglobin content in red blood cells, while administration of rHuEPO resulted in decrease in some erythrocyte-related parameters. As for iron-related parameters during erythropoiesis, JTZ-951 exhibited more efficient iron utilization compared to rHuEPO. A single dose of JTZ-951 resulted in decrease in hepcidin expression observed within 24 h after administration, but a single dose of rHuEPO did not. In a rat model of anemia of inflammation (also known as a model with functional iron-deficiency), JTZ-951 showed erythropoietic effect, in contrast with rHuEPO. These results suggest that, unlike rHuEPO, JTZ-951 stimulates erythropoiesis by increasing iron utilization, and improves anemia of inflammation.
JTZ-951 (Enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor
Eur J Pharmacol 2019 Sep 15;859:172532.PMID:31301309DOI:10.1016/j.ejphar.2019.172532.
JTZ-951 (Enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1-3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.
Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
Front Pharmacol 2022 Feb 24;13:837249.PMID:35281917DOI:10.3389/fphar.2022.837249.
Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and Enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.
Hemodialysis Clearance of Enarodustat (JTZ-951), an Oral Erythropoiesis Stimulating Agent, in Patients with End-Stage Renal Disease
Clin Pharmacol Drug Dev 2021 May;10(5):463-470.PMID:33788422DOI:10.1002/cpdd.923.
The dialysis clearance of Enarodustat (JTZ-951) was determined in patients (N = 6) with end-stage renal disease on hemodialysis. Enarodustat (5 mg PO) was administered before (day 1) and after hemodialysis (day 8) with pharmacokinetic assessments on the 2 occasions. Dialysis clearance was based on plasma and dialysate enarodustat concentrations. Fraction of administered dose recovered in dialysate, total predialyzer and postdialyzer plasma enarodustat concentrations, and total and unbound venous plasma concentrations were determined. Hemodialysis did not significantly affect overall total concentrations with similar mean area under the plasma concentration-time curve from time 0 to infinity (coefficient of variation) of 3350 (26.4%) and 3640 (20.9%) ng · h/mL on days 1 and 8, respectively, and mean terminal half-life was 9.35 (11.9%) and 9.96 (18.7%) hours on the 2 occasions. Mean maximum concentration was somewhat lower on day 1 compared to day 8 (404 vs 559 ng/mL); the difference did not significantly affect total exposure (area under the plasma concentration-time curve from time 0 to infinity). Plasma protein binding was high (>99%) with similar binding on the 2 occasions, and total pre- and postdialyzer enarodustat concentrations were similar. Plasma unbound enarodustat concentrations decreased during dialysis, with a postdialysis rebound presumably due to re-equilibration with peripheral tissues. Mean unbound area under the plasma concentration-time curve from time 0 to infinity was marginally lower (∼22%) on day 1 compared to day 8. Dialysis clearance (0.415 L/h) was insignificant relative to dialyzer plasma flow (∼20 L/h), and the fraction of administered dose recovered in dialysate was small (6.74% of dose) with low intersubject variability (coefficient of variation, 14.7%). Thus, enarodustat can be administered regardless of dialysis schedule, and dose supplementation is not required in patients with end-stage renal disease on hemodialysis.
A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study
Kidney Dis (Basel) 2021 Jul 5;7(6):494-502.PMID:34901195DOI:10.1159/000517053.
Introduction: Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. Methods: Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to <12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20-24 (noninferiority margin: -1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0-4. Results: The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was -0.12 g/dL (95% CI: -0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. Discussion/conclusion: Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.