Daprodustat | GSK1278863 | CAS#960539-70-2 | HIF-prolyl hydroxylase inhibitor

MedKoo Cat#: 206434 | Name: Daprodustat

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Daprodustat, also known as GSK1278863, is a novel HIF-prolyl hydroxylase inhibitor. Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease.

Chemical Structure

Daprodustat

CAS#960539-70-2

Theoretical Analysis

MedKoo Cat#: 206434

Name: Daprodustat

CAS#: 960539-70-2

Chemical Formula: C19H27N3O6

Exact Mass: 393.1900

Molecular Weight: 393.44

Elemental Analysis: C, 58.00; H, 6.92; N, 10.68; O, 24.40

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,850.00	Ready to ship
2g	USD 5,650.00	Ready to ship

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Related CAS #

No Data

Synonym

GSK1278863; GSK 1278863; GSK-1278863; Daprodustat

IUPAC/Chemical Name

(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine

InChi Key

RUEYEZADQJCKGV-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H27N3O6/c23-14(24)11-20-16(25)15-17(26)21(12-7-3-1-4-8-12)19(28)22(18(15)27)13-9-5-2-6-10-13/h12-13,15H,1-11H2,(H,20,25)(H,23,24)

SMILES Code

O=C(O)CNC(C(C(N1C2CCCCC2)=O)C(N(C3CCCCC3)C1=O)=O)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO (3mg/mL), not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#CRB61228

View CoA: current batch, Lot#C20R02B16

QC Data

View QC data: current batch, Lot#CRB61228

View QC data: current batch, Lot#C20R02B16

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor.

In vitro activity:

The immediate downstream effect of PHD (a family of HIF-prolyl hydroxylases) inhibition in a cellular context is HIFα subunit accumulation. Stabilization of HIF1α and HIF2α was determined by Western blot analysis of nuclear protein extracts after GSK1278863 treatment of Hep3B cells. Western blot analysis demonstrated that neither HIF1α nor HIF2α was detected in the vehicle-treated cells, and both HIF1α and HIF2α were visualized in the control-treated cells. Treatment with either 25 or 50 μM GSK1278863 for 6 hours resulted in the accumulation of both HIF1α and HIF2α subunits (Fig. 5). These results demonstrate that prolyl hydroxylase inhibition by GSK1278863 treatment of cells results in the immediate downstream effect of HIFα subunit stabilization. Reference: J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. https://jpet.aspetjournals.org/content/363/3/336.long

In vivo activity:

In vivo, normal female B6D2F1 mice were administered a single oral dose of GSK1278863 at 60 mg/kg, and blood samples were collected at intervals between 4 and 30 hours after dosing (n = 6 mice/time point for GSK1278863-treated mice; vehicle-treated mice were sampled at 6 hours only). After the treatment with GSK1278863, the EPO (erythropoietin) protein levels peaked at 12 hours after dosing (Fig. 6), representing an 11.2-fold increase with a mean plasma concentration of 1303 pg/ml. Additionally, the EPO values at all other time points remained elevated by 1.9- to 2.9-fold relative to the vehicle-treated mice. The VEGF (vascular endothelial growth factor) concentrations remained generally unchanged across the time course and were only slightly higher than those of vehicle-treated mice. These data indicate that a single 60 mg/kg dose of GSK1278863 results in a significant but transient increase in circulating levels of EPO, with minimal impact on VEGF concentrations. Reference: J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. https://jpet.aspetjournals.org/content/363/3/336.long

	Solvent	mg/mL	mM
Solubility
	DMF	3.0	7.63
	DMSO	14.2	36.02
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.27
	Ethanol	1.0	2.54

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 393.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C. Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia. J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. doi: 10.1124/jpet.117.242503. Epub 2017 Sep 19. PMID: 28928122.

In vitro protocol:

In vivo protocol:

1: Singh AK, Carroll K, McMurray JJV, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Więcek A, Blackorby A, Cizman B, Cobitz AR, Davies R, DiMino TL, Kler L, Meadowcroft AM, Taft L, Perkovic V; ASCEND-ND Study Group. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2313-2324. doi: 10.1056/NEJMoa2113380. Epub 2021 Nov 5. PMID: 34739196. 2: Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Więcek A, Blackorby A, Cizman B, Cobitz AR, Davies R, Dole J, Kler L, Meadowcroft AM, Zhu X, McMurray JJV; ASCEND-D Study Group. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2325-2335. doi: 10.1056/NEJMoa2113379. Epub 2021 Nov 5. PMID: 34739194. 3: Singh AK, Cizman B, Carroll K, McMurray JJV, Perkovic V, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Wiecek A, Stankus N, Strutz F, Blackorby A, Cobitz AR, Meadowcroft AM, Paul G, Ranganathan P, Sedani S, Solomon S. Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022 Jun 1;182(6):592-602. doi: 10.1001/jamainternmed.2022.0605. PMID: 35377393; PMCID: PMC8981070. 4: Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Daprodustat. 2023 Feb 15. PMID: 36780413. 5: Dhillon S. Daprodustat: First Approval. Drugs. 2020 Sep;80(14):1491-1497. doi: 10.1007/s40265-020-01384-y. PMID: 32880805; PMCID: PMC7471535. 6: Coyne DW, Singh AK, Lopes RD, Bailey CK, DiMino TL, Huang C, Connaire J, Rastogi A, Kim SG, Orias M, Shah S, Patel V, Cobitz AR, Wanner C. Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial. Clin J Am Soc Nephrol. 2022 Sep;17(9):1325-1336. doi: 10.2215/CJN.00550122. Epub 2022 Aug 2. PMID: 35918106; PMCID: PMC9625096. 7: Iso T, Matsue Y, Mizukami A, Tokano T, Isoda K, Suwa S, Miyauchi K, Yanagisawa N, Okumura Y, Minamino T. Daprodustat for anaemia in patients with heart failure and chronic kidney disease: A randomized controlled study. ESC Heart Fail. 2022 Dec;9(6):4291-4297. doi: 10.1002/ehf2.14109. Epub 2022 Aug 18. PMID: 35983622; PMCID: PMC9773652. 8: Fatima K, Ahmed W, Fatimi AS, Mahmud O, Mahar MU, Ali A, Aamir SR, Nasim MT, Islam MB, Maniya MT, Azim D, Marsia S, Almas T. Evaluating the safety and efficacy of daprodustat for anemia of chronic kidney disease: a meta-analysis of randomized clinical trials. Eur J Clin Pharmacol. 2022 Dec;78(12):1867-1875. doi: 10.1007/s00228-022-03395-y. Epub 2022 Oct 5. PMID: 36195739. 9: Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T, Endo Y, Hara K, Cobitz AR. Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial. Clin J Am Soc Nephrol. 2020 Aug 7;15(8):1155-1165. doi: 10.2215/CJN.16011219. Epub 2020 Jul 28. PMID: 32723804; PMCID: PMC7409739. 10: Nangaku M, Hamano T, Akizawa T, Tsubakihara Y, Nagai R, Okuda N, Kurata K, Nagakubo T, Jones NP, Endo Y, Cobitz AR. Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial. Am J Nephrol. 2021;52(1):26-35. doi: 10.1159/000513103. Epub 2021 Feb 9. PMID: 33561857; PMCID: PMC8117260. 11: Beninger P. Daprodustat. Clin Ther. 2023 May;45(5):480-481. doi: 10.1016/j.clinthera.2023.04.009. Epub 2023 May 6. PMID: 37156672. 12: Daprodustat. Am J Health Syst Pharm. 2023 May 24;80(11):639-642. doi: 10.1093/ajhp/zxad049. PMID: 37026612. 13: Johansen KL, Cobitz AR, Singh AK, Macdougall IC, Lopes RD, Obrador GT, Kovesdy CP, Israni R, Jha V, Okoro T, Sprys M, Jolly S, Lindsay AC, Bhatt P, Camejo RR, Keeley T, Cizman B, Wheeler DC. The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease. Kidney Int. 2023 Jun;103(6):1180-1192. doi: 10.1016/j.kint.2023.02.019. Epub 2023 Mar 2. PMID: 36868377. 14: Labes R, Brinkmann L, Kulow VA, Roegner K, Mathia S, Balcerek B, Persson PB, Rosenberger C, Fähling M. Daprodustat prevents cyclosporine-A-mediated anemia and peritubular capillary loss. Kidney Int. 2022 Oct;102(4):750-765. doi: 10.1016/j.kint.2022.04.025. Epub 2022 May 26. PMID: 35643373. 15: Xie D, Wang J, Wu X, Li M. Effect of daprodustat on anemia in patients with chronic kidney disease: a meta-analysis. Int Urol Nephrol. 2018 Dec;50(12):2201-2206. doi: 10.1007/s11255-018-1940-8. Epub 2018 Aug 2. PMID: 30073615. 16: Fadlalmola H, Al-Sayaghi K, Al-Hebshi A, Aljohani M, Albalawi M, Kashari O, Alem A, Alrasheedy M, Balelah S, Almuteri F, Alyamani A, Alwasaidi T. Efficacy of Different Doses of Daprodustat for Anemic Non-dialysis Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis. J Clin Med. 2022 May 11;11(10):2722. doi: 10.3390/jcm11102722. PMID: 35628849; PMCID: PMC9145143. 17: Ishii T, Tanaka T, Nangaku M. Profile of Daprodustat in the Treatment of Renal Anemia Due to Chronic Kidney Disease. Ther Clin Risk Manag. 2021 Feb 17;17:155-163. doi: 10.2147/TCRM.S293879. PMID: 33628028; PMCID: PMC7898206. 18: Allison SJ. Daprodustat for anaemia in CKD. Nat Rev Nephrol. 2022 Jan;18(1):3. doi: 10.1038/s41581-021-00515-2. PMID: 34824467. 19: Mahar KM, Shaddinger BC, Ramanjineyulu B, Andrews S, Caltabiano S, Lindsay AC, Cobitz AR. Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function. Clin Pharmacol Drug Dev. 2022 May;11(5):562-575. doi: 10.1002/cpdd.1090. Epub 2022 Mar 30. PMID: 35355447; PMCID: PMC9310628. 20: Slomski A. Oral Daprodustat Treats Anemia in Chronic Kidney Disease. JAMA. 2022 Feb 22;327(8):710. doi: 10.1001/jama.2022.1534. PMID: 35191925.