Desidustat
(Synonyms: ZYAN1) 目录号 : GC32449
An inhibitor of HIF-PH
Cas No.:1616690-16-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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Desidustat is an inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH).1 It reduces levels of hypoxia-inducible factor-1α (HIF-1α), a transcription factor regulated by HIF-PH enzymes, in rat liver and kidney. Desidustat increases the expression of the red blood cell- and iron transport-related genes Epo, Fpn1, and Hamp in rat liver in a model of anemia induced by peptidoglycan-polysaccharide (PGPS).2 It increases plasma levels of erythropoietin in rats by 10.3- to 40-fold when administered at doses of 15 and 30 mg/kg, respectively.1 Desidustat (15 and 30 mg/kg) also increases plasma levels of erythropoietin and hemoglobin, as well as the number of circulating red blood cells, in nephrectomized rats in a model of chronic kidney disease-induced anemia. It increases hemoglobin levels and the number of circulating red blood cells in a mouse model of anemia induced by the DNA-crosslinking agent cisplatin .
1.Jain, M.R., Joharapurkar, A.A., Pandya, V., et al.Pharmacological characterization of ZYAN1, a novel prolyl hydroxylase inhibitor for the treatment of anemiaDrug Res. (Stuttg.)66(2)107-112(2016) 2.Jain, M., Joharapurkar, A., Patel, V., et al.Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulationEur. J. Pharmacol.843113-120(2019)
| Cas No. | 1616690-16-4 | SDF | |
| 别名 | ZYAN1 | ||
| Canonical SMILES | O=C(O)CNC(C1=C(O)C2=C(N(OCC3CC3)C1=O)C=CC=C2)=O | ||
| 分子式 | C16H16N2O6 | 分子量 | 332.31 |
| 溶解度 | DMSO : ≥ 30 mg/mL (90.28 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 | 3.0092 mL | 15.0462 mL | 30.0924 mL |
| 5 mM | 0.6018 mL | 3.0092 mL | 6.0185 mL |
| 10 mM | 0.3009 mL | 1.5046 mL | 3.0092 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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Desidustat: First Approval
Drugs 2022 Jul;82(11):1207-1212.PMID:35834123DOI:10.1007/s40265-022-01744-w.
Desidustat (Oxemia鈩? is an orally bioavailable, small molecule, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor developed by Zydus Cadila for the treatment of anaemia associated with chronic kidney disease (CKD), COVID-2019 infections and chemotherapy induced anaemia. Desidustat inhibits prolyl hydroxylase domain enzymes, resulting in the stabilisation of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis. In March 2022, Desidustat received its first approval in India for the treatment of anaemia in adults with CKD who are either on dialysis or not on dialysis. Desidustat is in clinical development in China for the treatment of anaemia in patients with CKD, in Mexico for the management of COVID-2019 infections and in the USA for the treatment of chemotherapy induced anaemia. This article summarizes the milestones in the development of Desidustat leading to this first approval for anaemia associated with CKD.
Prolyl hydroxylase inhibitor Desidustat improves anemia in erythropoietin hyporesponsive state
Curr Res Pharmacol Drug Discov 2022 Apr 30;3:100102.PMID:35570856DOI:10.1016/j.crphar.2022.100102.
Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of Desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 鈥媘g/kg, IP, single dose) and turpentine oil (5 鈥媘L/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 鈥嬑糶/kg) and Desidustat (15 or 30 鈥媘g/kg) for eight weeks. Separately, rhEPO (1-5 鈥嬑糶/kg) was given to anemic rats to sustain the normal hemoglobin levels and Desidustat (15 鈥媘g/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 鈥嬑糶/kg) for two weeks and then Desidustat (15 鈥媘g/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for Desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1尾, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor Desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.
Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D)
Am J Nephrol 2022;53(5):343-351.PMID:35462369DOI:10.1159/000523949.
Background: A phase 3 study to assess the efficacy and safety of the Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency. Methods: DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] na茂ve or prior ESA users) and with baseline hemoglobin levels of 8.0-11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either Desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10-12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the Desidustat and the epoetin alfa groups from the baseline to evaluation period week 16-24. The key secondary efficacy endpoint was the number of patients with hemoglobin response. Results: The least square mean (standard error) change in hemoglobin from the baseline to week 16-24 was 0.95 (0.09) g/dL in the Desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: -0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the Desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the Desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of Desidustat compared to epoetin alfa. Conclusion: In this study, Desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).
Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND)
Am J Nephrol 2022;53(5):352-360.PMID:35462372DOI:10.1159/000523961.
Background: Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency. Methods: In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0-10.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either Desidustat 100 mg oral tablets thrice a week for 24 weeks or biosimilar darbepoetin subcutaneous injection 0.75 渭g/kg once in 2 weeks for 24 weeks. The primary outcome was the change from baseline in hemoglobin to evaluation period of Weeks 16-24. Key secondary outcomes included the number of patients with hemoglobin response, changes in the hepcidin levels, changes in the vascular endothelial growth factor (VEGF) levels, and changes in the lipid and lipoprotein profiles. Results: Hemoglobin change from baseline to Weeks 16-24 was 1.95 g/dL in the Desidustat group and 1.83 g/dL in the darbepoetin group (difference: 0.11 g/dL; 95% CI: -0.12, 0.34), which met prespecified non-inferiority margin (-0.75 g/dL). The hemoglobin responders were significantly higher (p = 0.0181) in the Desidustat group (196 [77.78%]) compared to the darbepoetin group (176 [68.48%]). The difference of change in hepcidin from baseline to Week 12 and Week 24 (p = 0.0032 at Week 12, p = 0.0016 at Week 24) and the difference of change in low-density lipoprotein from baseline to Week 24 (p value = 0.0269) between the two groups was statistically significant. The difference of change from baseline in VEGF to Weeks 12 and 24 between the two groups was not statistically significant. Conclusion: Desidustat is non-inferior to darbepoetin in the treatment of anemia due to non-dialysis dependent CKD and it is well-tolerated.
Nonclinical Pharmacokinetic Evaluation of Desidustat: a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia
Eur J Drug Metab Pharmacokinet 2022 Sep;47(5):725-740.PMID:35881329DOI:10.1007/s13318-022-00788-3.
Background and objectives: Desidustat is a novel prolyl hydroxylase domain (PHD) inhibitor for the treatment of anemia. The objective of this study was to investigate the pharmacokinetics and drug-drug interaction properties of Desidustat using in vitro and in vivo nonclinical models. Methods: In vitro, Caco2 cell permeability, plasma protein binding, metabolism, cytochrome P450 (CYP) inhibition, and CYP induction were examined. In vivo, pharmacokinetic studies of oral bioavailability in mice, rats, dogs and monkeys, dose linearity, tissue distribution, and excretion in rats were conducted. Results: In Caco-2 cells, the apparent permeability of Desidustat was high at low pH and low at neutral pH. The oral bioavailability (%F) of Desidustat was 43-100% with a median time to reach peak concentration (Tmax) of about 0.25-1.3 h across species. Desidustat displayed a low mean plasma clearance (CL) of 1.3-4.1 mL/min/kg (approximately 1.8-7.4% of hepatic blood flow), and the mean steady-state volume of distribution (Vss) was 0.2-0.4 L/kg (approximately 30-61% of the total body water). Desidustat showed a dose-dependent increase in exposures over the 15-100 mg/kg dose range. It was rapidly distributed in various tissues, with the highest tissue-to-blood ratio in the liver (1.8) and kidney (1.7). Desidustat showed high plasma protein binding and was metabolically stable in human liver microsomes, hepatocytes, and recombinant CYPs. It did not show significant inhibition of major drug-metabolizing CYP enzymes (IC50 > 300 碌M) or the potential to induce CYP1A2 and CYP3A4/5 (up to 100 碌M) in HepG2 cells. It may have minimal potential of clinical drug-drug interaction when used in combination with iron supplements or phosphate binders. Desidustat was primarily excreted unchanged in urine (25% of the oral dose) and bile (25% of the oral dose) in rats. The mean elimination half-life of Desidustat ranged from 1.0 to 5.3 h and 1.3 to 5.7 h across species after intravenous and oral administration, respectively. Conclusion: Taken together, Desidustat is well absorbed orally. It showed a dose-dependent increase in exposure, did not accumulate in tissue, and was eliminated via dual routes. It is metabolically stable, has minimal potential to cause clinical drug-drug interactions (DDIs), and demonstrates discriminable pharmacokinetic properties for the treatment of anemia.