Avatrombopag | AKR-501 | YM477 | E5501 | CAS#570406-98-3

MedKoo Cat#: 200127 | Name: Avatrombopag free base

Description:

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

Avatrombopag, also known as AKR-501, YM477, AS 1670542 or E5501, is a novel orally-active thrombopoietin (TPO) receptor agonist. AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. AKR-501 may be useful in the treatment of patients with thrombocytopenia. Avatrombopag was first approved in 2018.

Chemical Structure

Avatrombopag free base

CAS#570406-98-3 (free base)

Theoretical Analysis

MedKoo Cat#: 200127

Name: Avatrombopag free base

CAS#: 570406-98-3 (free base)

Chemical Formula: C29H34Cl2N6O3S2

Exact Mass: 648.1511

Molecular Weight: 649.65

Elemental Analysis: C, 53.61; H, 5.28; Cl, 10.91; N, 12.94; O, 7.39; S, 9.87

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 1,250.00	2 Weeks
500mg	USD 2,650.00	2 Weeks
1g	USD 3,750.00	2 Weeks
2g	USD 6,250.00	2 Weeks

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Related CAS #

677007-74-8 (maleate) 570406-98-3 (free base) 570403-17-7 (HCl)

Synonym

AKR501; AKR 501; AKR-501; YM477; YM-477; YM 477; AS 1670542; AS1670542; AS-1670542; E5501; E-5501; E 5501; Avatrombopag;

IUPAC/Chemical Name

(1-(3-chloro-5-((4-(4-chloro-2-thienyl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)-2-pyridyl)piperidine-4-carboxylic acid)

InChi Key

OFZJKCQENFPZBH-UHFFFAOYSA-N

InChi Code

InChI=1S/C29H34Cl2N6O3S2/c30-20-15-23(41-17-20)24-27(37-12-10-35(11-13-37)21-4-2-1-3-5-21)42-29(33-24)34-26(38)19-14-22(31)25(32-16-19)36-8-6-18(7-9-36)28(39)40/h14-18,21H,1-13H2,(H,39,40)(H,33,34,38)

SMILES Code

O=C(C1CCN(C2=NC=C(C(NC3=NC(C4=CC(Cl)=CS4)=C(N5CCN(C6CCCCC6)CC5)S3)=O)C=C2Cl)CC1)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, not in water

Shelf Life

>5 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

AKR-501, a novel, small-molecule thrombopoietin mimetic being investigated for the treatment of thrombocytopenia. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture AKR-501. AKR-501 is an investigational thrombopoietin receptor agonist that, based on preclinical studies, increases platelet production by stimulating megakaryocytic proliferation and differentiation. Eisai is currently conducting Phase II clinical trials of AKR-501 in the United States as a potential treatment for idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia associated with liver diseases (TLD), and has confirmed proof of concept in the clinical studies for ITP. In addition, Eisai will explore the compound's potential as a treatment for chemotherapy-induced thrombocytopenia (CIT).

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Avatrombopag is a thrombopoietin (TPO) receptor agonist with EC50=3.3 nM.

In vitro activity:

Granulocyte colony-stimulating factor-mobilized human peripheral blood CD34+ cells were cultured with AKR-501, TPO, or a combination of the two in serum-free liquid culture system. Both AKR-501 and TPO alone increased the number of megakaryocytes, and the maximum activities of AKR-501 and TPO were similar. Interestingly, in the presence of TPO concentrations producing maximal stimulation, the addition of AKR-501 increased the number of megakaryocytes to about 200% of that generated with TPO only. In the time course experiment, the combination of AKR-501 and TPO augmented the numbers of hematopoietic progenitor cells and colony-forming unit in culture in the early stages. Thus, the combination of AKR-501 and TPO enhanced not only the differentiation into megakaryocytes, but also the expansion of human hematopoietic progenitor cells. Further, AKR-501 did not inhibit TPO binding to the TPO receptor. This result indicated the possibility that AKR-501 and TPO may act simultaneously on the TPO receptor, and this could be responsible for their additive effect of on megakaryocytopoiesis. Reference: Exp Hematol. 2008 Oct;36(10):1337-42. https://www.exphem.org/article/S0301-472X(08)00209-9/fulltext

In vivo activity:

The in vivo platelet-increasing effect of AKR-501 was examined in human platelet producing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver CD34(+) cells. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. These results suggest that AKR-501 is an orally-active TPO receptor agonist that may be useful in the treatment of thrombocytopenia. Reference: Eur J Haematol. 2009 Apr;82(4):247-54. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.2008.01198.x

	Solvent	mg/mL	mM
Solubility
	DMSO	27.3	42.07

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 649.65 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. Fukushima-Shintani M, Suzuki K, Iwatsuki Y, Abe M, Sugasawa K, Hirayama F, Kawasaki T. AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis. Exp Hematol. 2008 Oct;36(10):1337-42. doi: 10.1016/j.exphem.2008.04.020. Epub 2008 Jul 10. PMID: 18619724.

In vitro protocol:

In vivo protocol:

1: Mladsi D, Barnett C, Aggarwal K, Vredenburg M, Dieterich D, Kim R. Cost- Effectiveness of Avatrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease. Clinicoecon Outcomes Res. 2020 Sep 14;12:515-526. doi: 10.2147/CEOR.S262772. PMID: 32982341; PMCID: PMC7500829. 2: Lim MY, Gilreath JA. Periprocedural use of avatrombopag for neurosurgical interventions: a strategy to avoid platelet utilization. Blood Adv. 2020 Sep 22;4(18):4438-4441. doi: 10.1182/bloodadvances.2020003045. PMID: 32936905; PMCID: PMC7509863. 3: Khemichian S, Terrault NA. Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease. Semin Thromb Hemost. 2020 Sep;46(6):682-692. doi: 10.1055/s-0040-1715451. Epub 2020 Aug 20. PMID: 32820479. 4: Dieterich DT, Bernstein D, Flamm S, Pockros PJ, Reau N. Review article: a treatment algorithm for patients with chronic liver disease and severe thrombocytopenia undergoing elective medical procedures in the United States. Aliment Pharmacol Ther. 2020 Aug 19. doi: 10.1111/apt.16044. Epub ahead of print. PMID: 32813292. 5: Nilles KM, Flamm SL. Thrombocytopenia in Chronic Liver Disease: New Management Strategies. Clin Liver Dis. 2020 Aug;24(3):437-451. doi: 10.1016/j.cld.2020.04.009. Epub 2020 May 31. PMID: 32620282. 6: Birocchi S, Podda GM, Manzoni M, Casazza G, Cattaneo M. Thrombopoietin receptor agonists for the treatment of primary immune thrombocytopenia: a meta- analysis and systematic review. Platelets. 2020 Apr 12:1-11. doi: 10.1080/09537104.2020.1745168. Epub ahead of print. PMID: 32281449. 7: Saab S, Bernstein D, Hassanein T, Kugelmas M, Kwo P. Treatment Options for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing a Scheduled Procedure. J Clin Gastroenterol. 2020 Jul;54(6):503-511. doi: 10.1097/MCG.0000000000001338. PMID: 32195771. 8: Poordad F, Terrault NA, Alkhouri N, Tian W, Allen LF, Rabinovitz M. Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies. Int J Hepatol. 2020 Jan 25;2020:5421632. doi: 10.1155/2020/5421632. PMID: 32047671; PMCID: PMC7003278. 9: Nilles KM, Caldwell SH, Flamm SL. Thrombocytopenia and Procedural Prophylaxis in the Era of Thrombopoietin Receptor Agonists. Hepatol Commun. 2019 Sep 4;3(11):1423-1434. doi: 10.1002/hep4.1423. PMID: 31701067; PMCID: PMC6824078. 10: Abdela J. Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag. Clin Med Insights Blood Disord. 2019 Oct 21;12:1179545X19875105. doi: 10.1177/1179545X19875105. Erratum in: Clin Med Insights Blood Disord. 2020 Jan 6;13:1179545X19900859. PMID: 31673229; PMCID: PMC6804364. 11: Hussar DA. New Drugs 2019, part 4. Nursing. 2019 Nov;49(11):34-43. doi: 10.1097/01.NURSE.0000585892.82614.f4. PMID: 31651773. 12: Cheloff AZ, Al-Samkari H. Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease. J Blood Med. 2019 Sep 5;10:313-321. doi: 10.2147/JBM.S191790. PMID: 31565009; PMCID: PMC6733339. 13: Witkowski M, Witkowska M, Robak T. Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs. Eur J Haematol. 2019 Dec;103(6):531-541. doi: 10.1111/ejh.13319. Epub 2019 Sep 18. PMID: 31449692. 14: Li C, Li X, Huang F, Yang J, Wu A, Wang L, Qin D, Zou W, Wu J. Efficacy and Safety of Avatrombopag in Patients With Thrombocytopenia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol. 2019 Jul 26;10:829. doi: 10.3389/fphar.2019.00829. PMID: 31402863; PMCID: PMC6677019. 15: Miller JB, Figueroa EJ, Haug RM, Shah NL. Thrombocytopenia in Chronic Liver Disease and the Role of Thrombopoietin Agonists. Gastroenterol Hepatol (N Y). 2019 Jun;15(6):326-332. PMID: 31391802; PMCID: PMC6676354. 16: Xu H, Cai R. Avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease. Expert Rev Clin Pharmacol. 2019 Sep;12(9):859-865. doi: 10.1080/17512433.2019.1649137. Epub 2019 Aug 5. PMID: 31352834. 17: Hussar DA, Kludjian GA. Prucalopride succinate, Fostamatinib disodium hexahydrate, Avatrombopag maleate, and Lusutrombopag. J Am Pharm Assoc (2003). 2019 Jul-Aug;59(4):601-604. doi: 10.1016/j.japh.2019.05.013. PMID: 31296323. 18: Dou X, Yang R. Current and emerging treatments for immune thrombocytopenia. Expert Rev Hematol. 2019 Sep;12(9):723-732. doi: 10.1080/17474086.2019.1636644. Epub 2019 Jul 4. PMID: 31237783. 19: Clemons Bankston P, Al-Horani RA. New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations. Int J Mol Sci. 2019 Jun 20;20(12):3013. doi: 10.3390/ijms20123013. PMID: 31226783; PMCID: PMC6628068. 20: Saab S, Brown RS Jr. Management of Thrombocytopenia in Patients with Chronic Liver Disease. Dig Dis Sci. 2019 Oct;64(10):2757-2768. doi: 10.1007/s10620-019-05615-5. Epub 2019 Apr 22. PMID: 31011942.