Avatrombopag

Avatrombopag
Clinical data
Pronunciation	a" va trom' boe pag
Trade names	Doptelet
AHFS/Drugs.com	Monograph
MedlinePlus	a618032
License data	US DailyMed: Avatrombopag;
Pregnancy; category	AU: B3;
Routes of; administration	By mouth
ATC code	B02BX08 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; US: ℞-only; EU: Rx-only; In general: ℞ (Prescription only);
Identifiers
	IUPAC name 1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid;
CAS Number	570406-98-3 ;
PubChem CID	9852519;
DrugBank	DB11995 ;
ChemSpider	8028230 ;
UNII	3H8GSZ4SQL;
KEGG	D10306; as salt: D10307;
ChEMBL	ChEMBL2103883 ;
CompTox Dashboard (EPA)	DTXSID30205667 ;
Chemical and physical data
Formula	C29H34Cl2N6O3S2
Molar mass	649.65 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CCC(CC1)N2CCN(CC2)C3=C(N=C(S3)NC(=O)C4=CC(=C(N=C4)N5CCC(CC5)C(=O)O)Cl)C6=CC(=CS6)Cl;
	InChI 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) ; Key:OFZJKCQENFPZBH-UHFFFAOYSA-N;
	(what is this?)

Avatrombopag, sold under the brand name Doptelet, is a medication that is used for certain conditions that lead to thrombocytopenia (low platelets) such as thrombocytopenia associated with chronic liver disease in adults who are to undergo a planned medical or dental procedure.^[8]^[9] It was approved for medical use in the United States in May 2018,^[10]^[11] the European Union in June 2019,^[7] and Australia in January 2023.^[1]

It acts as a thrombopoietin receptor agonist.^[12]

Synthesis

The chemical synthesis of avatrombopag was recently reported:^[13]

The halogenation of 2-acetyl-4-chlorothiophene [34730-20-6] (1) gave 2-bromo-1-(4-chloro-2-thienyl)ethanone [677007-73-7] (2). Condensation with thiourea produced 4-(4-chlorothiophen-2-yl)-1,3-thiazol-2-amine [570407-10-2] (3). Halogenation with N-bromosuccinimide (NBS) in DMF have an intermediate which was used for nucleophilic aromatic substitution with 1-cyclohexylpiperazine [17766-28-8] (4) to provide [570407-42-0] (5). Schotten-Baumann reaction with 5,6-dichloronicotinic acid [41667-95-2] (6) gave the corresponding nicotinamide [570403-04-2] (7). A second nucleophilic aromatic substitution ethyl isonipecotate [1126-09-6] (8) gave [570403-14-4] (9). Subsequent saponification completed the synthesis of avatrombopag (10).

References

1 2 3 "Doptelet". Therapeutic Goods Administration (TGA). 30 January 2023. Archived from the original on 5 February 2023. Retrieved 8 April 2023.
↑ "Doptelet (Swedish Orphan Biovitrum Pty Ltd)". Therapeutic Goods Administration (TGA). 16 February 2023. Archived from the original on 27 March 2023. Retrieved 8 April 2023.
↑ "AusPAR: Doptelet". Therapeutic Goods Administration (TGA). 8 February 2024. Retrieved 31 March 2024.
↑ "Details for: Doptelet". Health Canada. 22 January 2024. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
↑ "Summary Basis of Decision for Doptelet". Health Canada. 17 May 2024. Retrieved 8 June 2024.
↑ "Doptelet- avatrombopag maleate tablet, film coated". DailyMed. 1 July 2021. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
1 2 "Doptelet EPAR". European Medicines Agency (EMA). 24 April 2019. Archived from the original on 22 May 2020. Retrieved 2 May 2020.
↑ Abdela J (2019). "Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag". Clinical Medicine Insights. Blood Disorders. 12 1179545X19875105. doi:10.1177/1179545X19875105. PMC 6804364. PMID 31673229.
↑ Markham A (November 2021). "Avatrombopag: A Review in Thrombocytopenia". Drugs. 81 (16): 1905–1913. doi:10.1007/s40265-021-01613-y. PMC 8610948. PMID 34709601.
↑ "FDA approves new drug for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure". U.S. Food and Drug Administration (FDA) (Press release). 21 May 2018. Archived from the original on 11 December 2019. Retrieved 2 May 2020.
↑ "Drug Approval Package: Doptelet (avatrombopag)". U.S. Food and Drug Administration (FDA). 28 June 2018. Archived from the original on 7 April 2021. Retrieved 2 May 2020.
↑ Kuter DJ (November 2021). "The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag". Blood Reviews. 53 100909. doi:10.1016/j.blre.2021.100909. PMID 34815110. S2CID 244285488.
↑ Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., DeForest, J. C., Morse, P. D., Mahapatra, S., O’Donnell, C. J. (8 October 2020). "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry. 63 (19): 10652–10704. doi:10.1021/acs.jmedchem.0c00345.

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[Doptelet_APMDS-1] 1 2 3 "Doptelet". Therapeutic Goods Administration (TGA). 30 January 2023. Archived from the original on 5 February 2023. Retrieved 8 April 2023.

[2] "Doptelet (Swedish Orphan Biovitrum Pty Ltd)". Therapeutic Goods Administration (TGA). 16 February 2023. Archived from the original on 27 March 2023. Retrieved 8 April 2023.

[3] "AusPAR: Doptelet". Therapeutic Goods Administration (TGA). 8 February 2024. Retrieved 31 March 2024.

[4] "Details for: Doptelet". Health Canada. 22 January 2024. Archived from the original on 3 March 2024. Retrieved 3 March 2024.

[5] "Summary Basis of Decision for Doptelet". Health Canada. 17 May 2024. Retrieved 8 June 2024.

[6] "Doptelet- avatrombopag maleate tablet, film coated". DailyMed. 1 July 2021. Archived from the original on 3 March 2024. Retrieved 3 March 2024.

[Doptelet_EPAR-7] 1 2 "Doptelet EPAR". European Medicines Agency (EMA). 24 April 2019. Archived from the original on 22 May 2020. Retrieved 2 May 2020.

[Abdela_2019-8] Abdela J (2019). "Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag". Clinical Medicine Insights. Blood Disorders. 12 1179545X19875105. doi:10.1177/1179545X19875105. PMC 6804364. PMID 31673229.

[Markham_2021-9] Markham A (November 2021). "Avatrombopag: A Review in Thrombocytopenia". Drugs. 81 (16): 1905–1913. doi:10.1007/s40265-021-01613-y. PMC 8610948. PMID 34709601.

[10] "FDA approves new drug for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure". U.S. Food and Drug Administration (FDA) (Press release). 21 May 2018. Archived from the original on 11 December 2019. Retrieved 2 May 2020.

[11] "Drug Approval Package: Doptelet (avatrombopag)". U.S. Food and Drug Administration (FDA). 28 June 2018. Archived from the original on 7 April 2021. Retrieved 2 May 2020.

[Kuter_2021-12] Kuter DJ (November 2021). "The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag". Blood Reviews. 53 100909. doi:10.1016/j.blre.2021.100909. PMID 34815110. S2CID 244285488.

[13] Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., DeForest, J. C., Morse, P. D., Mahapatra, S., O’Donnell, C. J. (8 October 2020). "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry. 63 (19): 10652–10704. doi:10.1021/acs.jmedchem.0c00345.

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