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Technical details about Lusutrombopag, learn more about the structure, uses, toxicity, action, side effects and more

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2D Structure
1. Also known as: 1110766-97-6, Mulpleta, S-888711, 6ll5jfu42f, Rsc888711, (e)-3-[2,6-dichloro-4-[[4-[3-[(1s)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid
Molecular Formula
C29H32Cl2N2O5S
Molecular Weight
591.5  g/mol
InChI Key
NOZIJMHMKORZBA-KJCUYJGMSA-N
FDA UNII
6LL5JFU42F

Lusutrombopag is an orally bioavailable thrombopoietin receptor (TPOR) agonist developed by Shionogi & Company (Osaka, Japan). TPOR is a regulatory target site for endogenous thrombopoietin, which acts as a primary cytokine to promote megakaryocyte proliferation and differentiation, and affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. Thrombocytopenia, which indicates abnormally low levels of platelets, is a common complication related to chronic liver disease. This hematological abnormality, especially in cases of severe thrombocytopenia (platelet count <50,000/L), creates challenges to patients requiring invasive medical procedures where there is a significant risk for spontaneous bleeding. Lusutrombopag binds to the transmembrane domain of TPOR expressed on megakaryocytes, and causes the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells. In September 2015, lusutrombopag received its first global approval in Japan to reduce the need for platelet transfusion in adults with chronic liver disease and thrombocytopenia who are schedule to undergo an invasive medical procedure. Lusutrombopag was approved by the FDA on July 31st, 2018 for the same therapeutic indication under the market name Mulpleta. In two randomized, double-blind, placebo-controlled trials, patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure with a platelet count less than 50 x 10^9/L were administered lusutrombopag orally. Higher percentages (65-78%) of the patients receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure compared to those receiving placebo. Lusutrombopag is currently in phase III development in various European countries including Austria, Belgium, Germany, and the UK.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid
2.1.2 InChI
InChI=1S/C29H32Cl2N2O5S/c1-5-6-7-8-12-38-18(3)20-10-9-11-21(26(20)37-4)25-16-39-29(32-25)33-27(34)19-14-23(30)22(24(31)15-19)13-17(2)28(35)36/h9-11,13-16,18H,5-8,12H2,1-4H3,(H,35,36)(H,32,33,34)/b17-13+/t18-/m0/s1
2.1.3 InChI Key
NOZIJMHMKORZBA-KJCUYJGMSA-N
2.1.4 Canonical SMILES
CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl
2.1.5 Isomeric SMILES
CCCCCCO[C@@H](C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)/C=C(\C)/C(=O)O)Cl
2.2 Other Identifiers
2.2.1 UNII
6LL5JFU42F
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Mulpleta

2.3.2 Depositor-Supplied Synonyms

1. 1110766-97-6

2. Mulpleta

3. S-888711

4. 6ll5jfu42f

5. Rsc888711

6. (e)-3-[2,6-dichloro-4-[[4-[3-[(1s)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic Acid

7. (s,e)-3-(2,6-dichloro-4-((4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazol-2-yl)carbamoyl)phenyl)-2-methylacrylic Acid

8. (2e)-3-(2,6-dichloro-4-((4-(3-((1s)-1-(hexyloxy)ethyl)-2-methoxyphenyl)-1,3-thiazol-2-yl)carbamoyl)phenyl)-2-methylprop-2-enoic Acid

9. Lusutrombopag [inn]

10. Unii-6ll5jfu42f

11. Lusutrombopag [usan:inn]

12. Mulpleta (tn)

13. 2-propenoic Acid, 3-(2,6-dichloro-4-(((4-(3-((1s)-1-(hexyloxy)ethyl)-2-methoxyphenyl)-2-thiazolyl)amino)carbonyl)phenyl)-2-methyl-, (2e)-

14. S 888711

15. Lusutrombopags-888711

16. Lusutrombopag [mi]

17. Lusutrombopag [jan]

18. Lusutrombopag [usan]

19. Lusutrombopag [who-dd]

20. Schembl3062080

21. Schembl3062084

22. Chembl2107831

23. Lusutrombopag (jan/usan/inn)

24. Gtpl10032

25. Chebi:136051

26. Dtxsid701027951

27. Lusutrombopag [orange Book]

28. 2-propenoic Acid, 3-[2,6-dichloro-4-[[[4-[3-[(1s)-1-(hexyloxy)ethyl]-2-methoxyphenyl]-2-thiazolyl]amino]carbonyl]phenyl]-2-methyl-, (2e)-

29. Ex-a1290

30. Mfcd28502075

31. S6988

32. Zinc84759273

33. Cs-6137

34. Db13125

35. Ncgc00522464-01

36. (2e)-3-(2,6-dichloro-4-((4-(3-((1s)-1-(hexyloxy)ethyl)- 2-methoxyphenyl)-1,3-thiazol-2-yl)carbamoyl)phenyl)-2-methylprop-2-enoic Acid

37. Ac-30601

38. As-52368

39. Hy-19883

40. J3.505.027b

41. D10476

42. A927042

43. S888711

44. Q27265116

45. (e)-3-[2,6-dichloro-4-[4-[3-[(s)-1-hexyloxyethyl]-2-methoxyphenyl]thiazol-2-ylcarbamoyl]phenyl]-2-methylacrylic Acid

2.4 Create Date
2011-01-31
3 Chemical and Physical Properties
Molecular Weight 591.5 g/mol
Molecular Formula C29H32Cl2N2O5S
XLogP37.7
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count7
Rotatable Bond Count13
Exact Mass590.1408987 g/mol
Monoisotopic Mass590.1408987 g/mol
Topological Polar Surface Area126 Ų
Heavy Atom Count39
Formal Charge0
Complexity822
Isotope Atom Count0
Defined Atom Stereocenter Count1
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count1
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

Lusutrombopag is indicated for the treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.


FDA Label


Mulpleo is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures


Treatment of thrombocytopenia secondary to liver disease


5 Pharmacology and Biochemistry
5.1 Pharmacology

The AUC of lusutrombopag was found to correlate the increased platelet counts. Following administration of 3 mg daily dose in patients with chronic liver disease and thrombocytopenia, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) 10^9/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days. Lusutrombopag was not shown to induce any clinically significant QTc prolongation at a dose 8 times the recommended dosage.


5.2 ATC Code

B02BX


B - Blood and blood forming organs

B02 - Antihemorrhagics

B02B - Vitamin k and other hemostatics

B02BX - Other systemic hemostatics

B02BX07 - Lusutrombopag


5.3 Absorption, Distribution and Excretion

Absorption

Lusutrombopag is rapidly absorbed following oral administration. It exhibited a doseproportional pharmacokinetic profile over the single dose range of 1 mg to 50 mg, which was similar in both healthy subjects and those with chronic liver disease. A geometric mean (%CV) maximal concentration (Cmax) and area under the curve (AUC) in healthy subjects receiving 3 mg of lusutrombopag were 111 (20.4) ng/mL and 2931 (23.4) ng.hr/mL. The accumulation ratios of Cmax and AUC were approximately 2 with oncedaily multipledose administration, and steadystate plasma lusutrombopag concentrations were achieved after Day 5. The time to reach peak plasma concentrations (Tmax) were approximately 6 to 8 hours after oral administration in patients with chronic liver disease. Food consumption is not reported to affect the absorption and bioavailability of lusutrombopag.


Route of Elimination

About 1% of the administered dose of lusutrombopag undergoes urinary excretion. Fecal excretion accounted for 83% of the total dose, where 16% of the dose was excreted as unchanged parent compound.


Volume of Distribution

The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L.


Clearance

The approximate mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr.


5.4 Metabolism/Metabolites

CYP4 enzymes predominantly contribute to the metabolism of lusutrombopag, especially CYP4A11. Lusutrombopag is reported to mainly undergo - and -oxidation, as well as glucuronidation.


5.5 Biological Half-Life

In healthy adult subjects, the terminal elimination halflife (t1/2) was approximately 27 hours.


5.6 Mechanism of Action

Lusutrombopag mimics the biological actions of endogenous thrombopoietin (TPO) by acting as an agonist for the thrombopoietin receptor (TPOR) expressed on megakaryocytes. It binds to the transmembrane domain of the receptor and induces thrombocytopoiesis by targeting the same signal transduction system as that of endogenous TPO, which involves the activation of JAK and STAT pathways. It stimulates the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, which undergoes maturation to act as precursor cells for platelets. A single megakaryocyte produces and releases thousands of platelets upon maturation and series of remodeling events. Lusutrombopag displays high specificity towards human TPORs when compared to murine TPORs. Lusutrombopag may affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. One case of increased leukocyte and erythrocyte counts that prolonged for over 120 days was reported following administration in a patient with liver cirrhosis (LC) due to hepatitis C virus.


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