规格 | 价格 | 库存 | 数量 |
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10 mM * 1 mL in DMSO |
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1mg |
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5mg |
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25mg |
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50mg |
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100mg |
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250mg |
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500mg |
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1g |
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2g |
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Other Sizes |
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靶点 |
HIF-PHI/hypoxia-inducible factor-prolyl-hydroxylase
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体外研究 (In Vitro) |
在 PC12 细胞中,roxadustat(5-50 μM;6 小时)可显着减少 TBHP 诱导的细胞凋亡[2]。在 PC12 细胞中,roxadustat(50 μM;6 小时)可稳定 HIF-1α 蛋白表达[2]。
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体内研究 (In Vivo) |
改善脊髓损伤的恢复和保护运动神经元的存活是罗沙司他(50 mg/kg;腹腔注射;每天一次,持续 7 天)的两个好处[2]。
FG-4592/roxadustat给药还改善了小鼠模型脊髓损伤中神经元的恢复并提高了其存活率。包括特异性HIF-1α阻断剂YC-1在内的联合治疗下调了HIF-1α的表达,并部分消除了FG-4592的保护作用。综上所述,我们的研究结果表明,FG-4592在SCI恢复中的作用与HIF-1α的稳定和凋亡的抑制有关。总体而言,我们的研究表明,PHDI可能是SCI和人类中枢神经系统疾病后治疗干预的可行候选者[2]。 |
细胞实验 |
细胞凋亡分析[2]
细胞类型: PC12 细胞 测试浓度: 5、20、50 μM 孵育时间:6小时 实验结果:显着抑制TBHP诱导的细胞凋亡。 蛋白质印迹分析[2] 细胞类型: PC12 细胞 测试浓度: 50 μM 孵育时间:6小时 实验结果:稳定HIF-1α蛋白表达。 |
动物实验 |
Animal/Disease Models: 12-week female C57BL/6 mice[2]
Doses: 50 mg/ kg Route of Administration: intraperitoneal (ip)injection; daily for 7 days Experimental Results: Protected the survival of motor neurons and improved recovery from spinal cord injury. |
药代性质 (ADME/PK) |
Absorption, Distribution and Excretion
Roxadustat plasma exposure (AUC and Cmax) increases dose-proportionally within the recommended therapeutic dose range. In a three times per week dosing regimen, steady-state roxadustat plasma concentrations are achieved within one week (three doses) with minimal accumulation. Maximum plasma concentrations (Cmax) are usually achieved at two hours post dose in the fasted state. Administration of roxadustat with food decreased Cmax by 25% but did not alter AUC as compared with the fasted state. Following oral administration of radiolabelled roxadustat in healthy subjects, the mean recovery of radioactivity was 96% (50% in feces, 46% in urine). In feces, 28% of the dose was excreted as unchanged roxadustat. Less than 2% of the dose was recovered in urine as unchanged roxadustat. The blood-to-plasma ratio of roxadustat is 0.6. The apparent volume of distribution at steady-state is 24 L. The apparent total body clearance (CL/F) of roxadustat is 1.1 L/h in patients with CKD not on dialysis and 1.4 L/h in patients with CKD on dialysis. Metabolism / Metabolites _In vitro_, roxadustat is a substrate for CYP2C8 and UGT1A9 enzymes. Roxadustat is primarily metabolized to hydroxy-roxadustat and roxadustat O-glucuronide. Unchanged roxadustat was the major circulating component in human plasma and detectable metabolites in human plasma constituted less than 10% of total drug-related material exposure. No human-specific metabolites were observed but roxadustat O-glucuronide was detected in human urine sample. Biological Half-Life The mean effective half-life of roxadustat is approximately 15 hours in patients with CKD. |
毒性/毒理 (Toxicokinetics/TK) |
Protein Binding
Roxadustat is highly bound to human plasma proteins (approximately 99%), mainly to albumin. |
参考文献 |
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其他信息 |
Roxadustat is an N-acylglycine resulting from the formal condensation of the amino group of glycine with the carboxy group of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. It is an inhibitor of hypoxia inducible factor prolyl hydroxylase (HIF-PH). It has a role as an EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor and an EC 1.14.11.29 (hypoxia-inducible factor-proline dioxygenase) inhibitor. It is a member of isoquinolines, an aromatic ether and a N-acylglycine.
Roxadustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia associated with chronic kidney disease. It works by reducing the breakdown of the hypoxia-inducible factor (HIF), which is a transcription factor that stimulates red blood cell production in response to low oxygen levels. Roxadustat was first approved by the European Commission in August 2021. Roxadustat is an orally bioavailable, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), with potential anti-anemic activity. Upon administration, roxadustat binds to and inhibits HIF-PHI, an enzyme responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. This prevents HIF breakdown and promotes HIF activity. Increased HIF activity leads to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability, and boosts hemoglobin (Hb) levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Drug Indication Roxadustat is indicated for the treatment of adult patients with symptomatic anemia associated with chronic kidney disease (CKD). Evrenzo is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD). Treatment of anaemia due to chronic disorders Mechanism of Action Anemia is a common complication of chronic kidney disease that may be caused by reduced production of renal erythropoietin (EPO), functional iron deficiency due to increased levels of hepcidin, blood loss, reduced erythrocyte survival duration, and inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that induces several target oxygen-sensitive genes in response to low oxygen levels in the cellular environment, or hypoxia. Target genes are involved in erythropoiesis, such as those for EPO, EPO receptor, proteins promoting iron absorption, iron transport, and haem synthesis. Activation of the HIF pathway is an important adaptive responsive to hypoxia to increase red blood cell production. HIF is heterodimeric and contains an oxygen-regulated α-subunit. The α-subunit houses an oxygen-dependent degradation (ODD) domain that is regulated and hydroxylated by HIF-prolyl hydroxylase (HIF-PHD) enzymes under normoxic cellular conditions. HIF-PHD enzymes play a crucial role in maintaining a balance between oxygen availability and HIF activity. Roxadustat is a reversible and potent inhibitor of HIF-PHD enzymes: inhibition of HIF-PHD leads to the accumulation of functional HIF, an increase in plasma endogenous EPO production, enhanced erythropoiesis, and indirect suppression of hepcidin, which is an iron regulator protein that is increased during inflammation in chronic kidney disease. Roxadustat can also regulate iron transporter proteins and regulates iron metabolism by increasing serum transferrin, intestinal iron absorption and the release of stored iron in patients with anemia associated with dialysis-dependent or dialysis-independent CKD. Overall, roxadustat improves iron bioavailability, increases Hb production, and increases red cell mass. Pharmacodynamics Roxadustat dose-dependently improves iron bioavailability, increases hemoglobin production, and increases red blood cell mass in patients with anemia. In non-dialysis-dependent CKD patients with anemia, roxadustat maintained Hb for up to 2 years. It has a comparable efficacy to erythropoietin-stimulating agents in achieving Hb response. Roxadustat also reduces cholesterol levels from baseline, regardless of the use of statins or other lipid-lowering agents. |
分子式 |
C19H16N2O5
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分子量 |
352.34100
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精确质量 |
352.105
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元素分析 |
C, 64.77; H, 4.58; N, 7.95; O, 22.70
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CAS号 |
808118-40-3
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相关CAS号 |
Roxadustat-d5;2043026-13-5; 1537179-95-5 (potassium); 808118-40-3 (free); 1537180-01-0 (HCl); 1537179-94-4 (sodium); 1537180-03-2 (mesylate)
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PubChem CID |
11256664
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外观&性状 |
Light yellow to green yellow solid powder
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密度 |
1.4±0.1 g/cm3
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沸点 |
684.3±55.0 °C at 760 mmHg
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熔点 |
199-215°C
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闪点 |
367.6±31.5 °C
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蒸汽压 |
0.0±2.2 mmHg at 25°C
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折射率 |
1.674
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LogP |
3.9
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tPSA |
108.75
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氢键供体(HBD)数目 |
3
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氢键受体(HBA)数目 |
6
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可旋转键数目(RBC) |
5
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重原子数目 |
26
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分子复杂度/Complexity |
508
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定义原子立体中心数目 |
0
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InChi Key |
YOZBGTLTNGAVFU-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C19H16N2O5/c1-11-15-9-13(26-12-5-3-2-4-6-12)7-8-14(15)18(24)17(21-11)19(25)20-10-16(22)23/h2-9,24H,10H2,1H3,(H,20,25)(H,22,23)
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化学名 |
(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine
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别名 |
Roxadustat; ASP1517; ASP 1517; Roxadustat (FG-4592); N-[(4-Hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]glycine; ASP-1517; FG-4592; FG4592; FG-4592;
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HS Tariff Code |
2934.99.9001
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存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
运输条件 |
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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溶解度 (体外实验) |
DMSO : ≥ 100 mg/mL (~283.82 mM)
H2O : < 0.1 mg/mL |
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溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (7.10 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加,逐一添加), 澄清溶液。
例如,若需制备1 mL的工作液,可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中,混匀;然后向上述溶液中加入50 μL Tween-80,混匀;加入450 μL生理盐水定容至1 mL。 *生理盐水的制备:将 0.9 g 氯化钠溶解在 100 mL ddH₂O中,得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (7.10 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加,逐一添加), 澄清溶液。 例如,若需制备1 mL的工作液,可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (7.10 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加,逐一添加), 澄清溶液。 配方 4 中的溶解度: 5 mg/mL (14.19 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加,逐一添加), 悬浊液; 超声助溶。 *生理盐水的制备:将 0.9 g 氯化钠溶解在 100 mL ddH₂O中,得到澄清溶液。 1、请先配制澄清的储备液(如:用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液,按从左到右的顺序依次添加助溶剂,澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明,并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀/澄清;向上述体系中加入50 μL Tween-80,混合均匀/澄清;然后继续加入450 μL ddH2O (或 saline)定容至 1 mL; 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出,可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果,工作液请现配现用! 6、如不确定怎么将母液配置成体内动物实验的工作液,请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
制备储备液 | 1 mg | 5 mg | 10 mg | |
1 mM | 2.8382 mL | 14.1908 mL | 28.3817 mL | |
5 mM | 0.5676 mL | 2.8382 mL | 5.6763 mL | |
10 mM | 0.2838 mL | 1.4191 mL | 2.8382 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液):对于大多数产品,InvivoChem推荐用DMSO配置母液 (比如:5、10、20mM或者10、20、50 mg/mL浓度),个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息,或者很难将产品溶解在溶液中,请联系我们;
3、建议使用下列计算器进行相关计算(摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等);
4、母液配好之后,将其分装到常规用量,并储存在-20°C或-80°C,尽量减少反复冻融循环。
计算结果:
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)。如该浓度超过该批次药物DMSO溶解度,请首先与我们联系。
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 ddH2O,混匀澄清。
(1) 请确保溶液澄清之后,再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶;
(2) 一定要按顺序加入溶剂 (助溶剂) 。
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT05970172 | Recruiting | Drug: Roxadustat | Chronic Kidney Disease Renal Anemia |
Astellas Pharma Global Development, Inc. |
January 16, 2024 | Phase 3 |
NCT04076943 | Completed Has Results |
Drug: Roxadustat | Chemotherapy Induced Anemia | FibroGen | August 20, 2019 | Phase 2 |
NCT06020833 | Not yet recruiting | Drug: Roxadustat in combination with retinoic acid |
Myelodysplastic Syndromes | Peking Union Medical College Hospital | August 2023 | Phase 1 Phase 2 |
NCT04454879 | Completed | Drug: Roxadustat | Renal Anemia | Peking University First Hospital | July 1, 2020 | Phase 4 |
Figure 1Study scheme. Abbreviations: IV, intravenous; pt, patient; TIW, thrice weekly. td> |
Figure 2Hemoglobin levels over time (6 weeks) by treatment group. (A) Hb levels over time by dose cohort for participants randomly assigned to 6 weeks of treatment in part 1. Hb level responders are defined as the number (percent) of patients whose Hb levels did not decrease by >0.5 g/dL from their baseline (primary efficacy end point in part 1). (B) Least squares mean Hb levels over time (19 weeks), roxadustat-treated versus epoetin alfa–treated patients. Closed diamonds are roxadustat (n = 61); open circles are epoetin alfa (n = 22). ∗P values are from Fisher exact test (2 sided) comparing roxadustat with epoetin alfa. Error bars signify standard error (SE) of the mean. td> |
Figure 3Baseline C-reactive protein (CRP) levels are correlated with (A) pre-enrollment epoetin alfa but not (B) roxadustat maintenance dose requirements. ∗N = 49: all participants randomly assigned to 19 weeks of roxadustat treatment and dosed beyond 12 weeks (maintenance phase) with valid baseline epoetin alfa dose data and valid baseline and average last 7 of 19 weeks of CRP data. Thus, this analysis did not include the 9 patients discontinued from roxadustat treatment for lack of efficacy (see Fig S1). Baseline CRP level was the average of the last 3 values prior to the first dose of study drug. CRP is plotted on the x-axis using a logarithmic scale. Abbreviation: LR, linear regression. td> |