Enarodustat | CAS#1262132-81-9 | antianaemic

MedKoo Cat#: 561113 | Name: Enarodustat

Description:

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

Enarodustat, also known as JTZ-951, is a prolyl hydroxylase inhibitor. JTZ-951 (enarodustat) stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor. Enarodustat increases endogenous erythropoietin levels in the treatment of anemia associated with chronic kidney disease (CKD). JTZ-951 induces erythropoiesis without affecting VEGF function. JTZ-951 may be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.

Chemical Structure

Enarodustat

CAS#1262132-81-9 (free base)

Theoretical Analysis

MedKoo Cat#: 561113

Name: Enarodustat

CAS#: 1262132-81-9 (free base)

Chemical Formula: C17H16N4O4

Exact Mass: 340.1172

Molecular Weight: 340.34

Elemental Analysis: C, 60.00; H, 4.74; N, 16.46; O, 18.80

Price and Availability

Size	Price	Availability
25mg	USD 250.00	2 Weeks
50mg	USD 450.00	2 Weeks
100mg	USD 750.00	2 Weeks
200mg	USD 1,350.00	2 Weeks
500mg	USD 2,850.00	2 Weeks
1g	USD 4,250.00	2 Weeks
2g	USD 6,950.00	2 Weeks

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Related CAS #

1262132-81-9 (free base) 1262131-60-1 (HCl) 1262133-55-0 (disodium)

Synonym

Enarodustat; JTZ-951; JTZ 951; JTZ951;

IUPAC/Chemical Name

N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine

InChi Key

NALAUGMPMIVAOW-UHFFFAOYSA-N

InChi Code

InChI=1S/C17H16N4O4/c22-13-8-12(7-6-11-4-2-1-3-5-11)21-16(19-10-20-21)15(13)17(25)18-9-14(23)24/h1-5,8,10,22H,6-7,9H2,(H,18,25)(H,23,24)

SMILES Code

O=C(O)CNC(C1=C(O)C=C(CCC2=CC=CC=C2)N3C1=NC=N3)=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

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

Instruction

View handling instruction

Biological target:

Enarodustat is a potent and orally active factor prolyl hydroxylase inhibitor, with an EC50 of 0.22 μM.

In vitro activity:

To evaluate the effect of JTZ-951 in this model, this study added JTZ-951 on day 0 and checked HIF-1α and HIF-2α protein stabilization, α-SMA expression, and hypoxic EPO upregulation. The addition of JTZ-951 stabilized HIF-1α and HIF-2α proteins (Fig. 2A), suppressed α-SMA expression (Fig. 2B), and maintained the hypoxic induction of EPO (Fig. 2C). Furthermore, JTZ-951 also reversed α-SMA upregulation on day 8 when added on day 6 (Fig. 2D). Reference: Am J Physiol Renal Physiol. 2020 Jan 1;318(1):F14-F24. https://pubmed.ncbi.nlm.nih.gov/31630548/

In vivo activity:

Glomerulomegaly was noticeable in group B compared with group A, which was reversed by enarodustat (Figure 9e). Transcriptome analysis of renal tissue in alloxan-induced diabetic mice showed symmetric metabolism alterations (diabetes vs. enarodustat) in the same way as in the STZ-induced diabetic rat model (Figure 10): fatty-acid metabolism was upregulated by diabetes, whereas glucose metabolism was upregulated by enarodustat. Furthermore, amino-acid metabolism was upregulated by diabetes and downregulated by enarodustat. Thus, enarodustat counteracted renal energy metabolism alterations occurring in the early stages of DKD in the alloxan-induced diabetic mouse model as well as in the STZ-induced diabetic rat model. Reference: Kidney Int. 2020 May;97(5):934-950. https://pubmed.ncbi.nlm.nih.gov/32171449/

	Solvent	mg/mL	mM
Solubility
	DMSO	60.4	177.59
	DMSO:PBS (pH 7.2) (1:4)	0.2	0.59
	DMF	30.0	88.15
	Ethanol	25.0	73.46

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 340.34 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. Wakashima T, Tanaka T, Fukui K, Komoda Y, Shinozaki Y, Kobayashi H, Matsuo A, Nangaku M. JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors. Am J Physiol Renal Physiol. 2020 Jan 1;318(1):F14-F24. doi: 10.1152/ajprenal.00323.2019. Epub 2019 Oct 21. PMID: 31630548. 2. Fukui K, Shinozaki Y, Kobayashi H, Deai K, Yoshiuchi H, Matsui T, Matsuo A, Matsushita M, Tanaka T, Nangaku M. 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. doi: 10.1016/j.ejphar.2019.172532. Epub 2019 Jul 10. PMID: 31301309. 3. Hasegawa S, Tanaka T, Saito T, Fukui K, Wakashima T, Susaki EA, Ueda HR, Nangaku M. The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease. Kidney Int. 2020 May;97(5):934-950. doi: 10.1016/j.kint.2019.12.007. Epub 2019 Dec 25. PMID: 32171449. 4. Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, Ueda M, Fukui K, Shimizu A, Inagi R, Yamauchi T, Kadowaki T, Nangaku M. Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice. J Am Soc Nephrol. 2020 Mar;31(3):560-577. doi: 10.1681/ASN.2019060582. Epub 2020 Jan 29. PMID: 31996409; PMCID: PMC7062217.

In vitro protocol:

In vivo protocol:

1. Hasegawa S, Tanaka T, Saito T, Fukui K, Wakashima T, Susaki EA, Ueda HR, Nangaku M. The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease. Kidney Int. 2020 May;97(5):934-950. doi: 10.1016/j.kint.2019.12.007. Epub 2019 Dec 25. PMID: 32171449. 2. Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, Ueda M, Fukui K, Shimizu A, Inagi R, Yamauchi T, Kadowaki T, Nangaku M. Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice. J Am Soc Nephrol. 2020 Mar;31(3):560-577. doi: 10.1681/ASN.2019060582. Epub 2020 Jan 29. PMID: 31996409; PMCID: PMC7062217.

1: Markham A. Enarodustat: First Approval. Drugs. 2021 Jan;81(1):169-174. doi: 10.1007/s40265-020-01444-3. PMID: 33320297. 2: Fujikawa R, Nagao Y, Fujioka M, Akizawa T. Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence. Ther Apher Dial. 2022 Aug;26(4):679-693. doi: 10.1111/1744-9987.13820. Epub 2022 Mar 7. PMID: 35218616; PMCID: PMC9539985. 3: Fukui K, Tanaka T, Nangaku M. Enarodustat to treat anemia in chronic kidney disease. Drugs Today (Barc). 2021 Aug;57(8):491-497. doi: 10.1358/dot.2021.57.8.3304877. PMID: 34405206. 4: Hasegawa S, Tanaka T, Saito T, Fukui K, Wakashima T, Susaki EA, Ueda HR, Nangaku M. The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease. Kidney Int. 2020 May;97(5):934-950. doi: 10.1016/j.kint.2019.12.007. Epub 2019 Dec 25. PMID: 32171449. 5: Mima A. Enarodustat Treatment for Renal Anemia in Patients With Non-dialysis Chronic Kidney Disease. In Vivo. 2023 Mar-Apr;37(2):825-829. doi: 10.21873/invivo.13148. PMID: 36881056; PMCID: PMC10026677. 6: Chen J, Shou X, Xu Y, Jin L, Zhu C, Ye X, Mei Z, Chen P. A network meta- analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease. Aging (Albany NY). 2023 Mar 27;15(6):2237-2274. doi: 10.18632/aging.204611. Epub 2023 Mar 27. PMID: 36988549; PMCID: PMC10085583. 7: Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, Ueda M, Fukui K, Shimizu A, Inagi R, Yamauchi T, Kadowaki T, Nangaku M. Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice. J Am Soc Nephrol. 2020 Mar;31(3):560-577. doi: 10.1681/ASN.2019060582. Epub 2020 Jan 29. PMID: 31996409; PMCID: PMC7062217. 8: Zheng Q, Yang H, Sun L, Wei R, Fu X, Wang Y, Huang Y, Liu YN, Liu WJ. Efficacy and safety of HIF prolyl-hydroxylase inhibitor vs epoetin and darbepoetin for anemia in chronic kidney disease patients not undergoing dialysis: A network meta-analysis. Pharmacol Res. 2020 Sep;159:105020. doi: 10.1016/j.phrs.2020.105020. Epub 2020 Jun 16. PMID: 32561478. 9: Pai SM, Yamada H. 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. doi: 10.1002/cpdd.923. Epub 2021 Mar 31. PMID: 33788422. 10: Akizawa T, Nangaku M, Yamaguchi T, Arai M, Koretomo R, Maeda K, Miyazawa Y, Hirakata H. Enarodustat, Conversion and Maintenance Therapy for Anemia in Hemodialysis Patients: A Randomized, Placebo-Controlled Phase 2b Trial Followed by Long-Term Trial. Nephron. 2019;143(2):77-85. doi: 10.1159/000500487. Epub 2019 May 22. PMID: 31117088; PMCID: PMC6878752. 11: Akizawa T, Nangaku M, Yamaguchi T, Koretomo R, Maeda K, Miyazawa Y, Hirakata H. A Phase 3 Study of Enarodustat in Anemic Patients with CKD not Requiring Dialysis: The SYMPHONY ND Study. Kidney Int Rep. 2021 May 12;6(7):1840-1849. doi: 10.1016/j.ekir.2021.04.037. PMID: 34307978; PMCID: PMC8258589. 12: Akizawa T, Nangaku M, Yamaguchi T, Koretomo R, Maeda K, Miyazawa Y, Hirakata H. 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. doi: 10.1159/000517053. PMID: 34901195; PMCID: PMC8613566. 13: Miao M, Wu M, Li Y, Zhang L, Jin Q, Fan J, Xu X, Gu R, Hao H, Zhang A, Jia Z. Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases. Front Pharmacol. 2022 Feb 24;13:837249. doi: 10.3389/fphar.2022.837249. PMID: 35281917; PMCID: PMC8908211. 14: Pai SM, Kambhampati SRP, Naruhashi S, Yamada H. Pharmacokinetics of Enarodustat in Non-Japanese and Japanese Healthy Subjects and in Patients With End-Stage Renal Disease on Hemodialysis. Clin Pharmacol Drug Dev. 2023 Jul;12(7):683-690. doi: 10.1002/cpdd.1252. Epub 2023 May 19. PMID: 37203396. 15: Shinozaki Y, Fukui K, Kobayashi H, Yoshiuchi H, Matsuo A, Matsushita M. 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. doi: 10.1016/j.ejphar.2021.173990. Epub 2021 Feb 28. PMID: 33657422. 16: Akizawa T, Nangaku M, Yamaguchi T, Arai M, Koretomo R, Matsui A, Hirakata H. A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial. Am J Nephrol. 2019;49(2):165-174. doi: 10.1159/000496929. Epub 2019 Jan 30. PMID: 30699415; PMCID: PMC6481254. 17: Pai S, Huang MQ, Maki K, Waldron M, Yoshikawa T, Keller T, Burnett J. A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jun 30;1176:122754. doi: 10.1016/j.jchromb.2021.122754. Epub 2021 May 13. PMID: 34052557. 18: Chen H, Cheng Q, Wang J, Zhao X, Zhu S. Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients. J Clin Pharm Ther. 2021 Aug;46(4):999-1009. doi: 10.1111/jcpt.13385. Epub 2021 Feb 21. PMID: 33615523. 19: Pai SM, Yamada H, Kleiman RB, Zhuo R, Huang QM, Koretomo R. Thorough QT/QTc Evaluation of the Cardiac Safety of Enarodustat (JTZ-951), an Oral Erythropoiesis-Stimulating Agent, in Healthy Adults. Clin Pharmacol Drug Dev. 2021 Aug;10(8):884-898. doi: 10.1002/cpdd.933. Epub 2021 Jun 23. PMID: 34159762. 20: Naruhashi S, Fujii T, Yamada H, Pai SM, Ninomiya N. Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease. J Clin Pharmacol. 2023 Feb;63(2):180-196. doi: 10.1002/jcph.2148. Epub 2022 Oct 7. PMID: 36057843.