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Fedratinib

Fedratinib

Synopsis, Chemistry

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Also known as: 936091-26-8, Tg-101348, Tg101348, Sar302503, Sar-302503, N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

Molecular Formula

C₂₇H₃₆N₆O₃S

Molecular Weight

524.7 g/mol

InChI Key

JOOXLOJCABQBSG-UHFFFAOYSA-N

FDA UNII

6L1XP550I6

Fedratinib is an orally bioavailable, small-molecule, ATP-competitive inhibitor of Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3; CD135; STK1; FLK2), with potential antineoplastic activity. Upon oral administration, fedratinib competes with wild-type JAK2 as well as mutated forms for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, inhibition of tumor cell proliferation and induction of tumor cell apoptosis. JAK2 is the most commonly mutated gene in bcr-abl-negative myeloproliferative disorders (MPDs). In addition, fedratinib targets, binds to and inhibits the activity of FLT3. This inhibits uncontrolled FLT3 signaling and results in the inhibition of proliferation in tumor cells overexpressing FLT3. FLT3, a class III receptor tyrosine kinase (RTK), is overexpressed or mutated in most B-lineage neoplasms and in acute myeloid leukemias and plays a key role in tumor cell proliferation.

1 2D Structure

Fedratinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide

2.1.2 InChI

InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)

2.1.3 InChI Key

JOOXLOJCABQBSG-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4

2.2 Other Identifiers

2.2.1 UNII

6L1XP550I6

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Fedratinib Dihydrochloride Monohydrate

2. Fedratinib Hydrochloride

3. Fedratinib Hydrochloride Monohydrate

4. Inrebic

5. N-tert-butyl-3-((5-methyl-2-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)pyrimidin-4-yl)amino) Benzenesulfonamide Dihydrochloride Monohydrate

6. N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino) Pyrimidin-4-ylamino)benzenesulfonamide

7. Sar-302503

8. Sar-302503a

9. Sar302503

10. Sar302503a

11. Tg-101348

12. Tg101348

2.3.2 Depositor-Supplied Synonyms

1. 936091-26-8

2. Tg-101348

3. Tg101348

4. Sar302503

5. Sar-302503

6. N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

7. Inrebic

8. Sar 302503

9. Tg 101348

10. Fedratinib (sar302503, Tg101348)

11. N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide

12. Tg101348 (sar302503)

13. Chembl1287853

14. 6l1xp550i6

15. 936091-26-8 (free Base)

16. N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide

17. Benzenesulfonamide, N-(1,1-dimethylethyl)-3-((5-methyl-2-((4-(2-(1-pyrrolidinyl)ethoxy)phenyl)amino)-4-pyrimidinyl)amino)-

18. N-tert-butyl-3-(5-methyl-2-(4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino)-pyrimidin-4-ylamino)-benzenesulfonamide

19. N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide

20. Fedratinib [usan]

21. Fedratinib [usan:inn]

22. Unii-6l1xp550i6

23. C27h36n6o3s

24. 2ta

25. Fedratinib [mi]

26. Fedratinib [inn]

27. Fedratinib (usan/inn)

28. Tg101348(fedratinib)

29. Fedratinib [who-dd]

30. Fedratinib (tg101348)

31. Mls006011155

32. N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide

33. Schembl263741

34. Gtpl5716

35. Chebi:91408

36. Dtxsid90239483

37. Ex-a170

38. Hms3295i03

39. Hms3656l19

40. Hms3744g17

41. Hms3868l03

42. Bcp02300

43. Bdbm50332294

44. Mfcd12922515

45. Nsc767600

46. Nsc800099

47. S2736

48. Zinc19862646

49. Akos015842621

50. Ccg-264990

51. Cs-0052

52. Db12500

53. Ex-5961

54. Nsc-767600

55. Nsc-800099

56. Sb14604

57. Ncgc00244252-01

58. Ncgc00244252-07

59. Ac-30260

60. As-16248

61. Da-40258

62. Hy-10409

63. Smr004702929

64. Db-079623

65. Ft-0705969

66. Ft-0763396

67. Ft-0766818

68. Sw218187-2

69. A25534

70. D10630

71. F17372

72. 091d268

73. J-523769

74. Q7670147

75. Brd-k12502280-001-01-5

76. 945381-69-1

77. N-tert-butyl-3-((5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)anilino(pyrimidin-4-yl)amino)benzenesulfonamide

78. N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide

79. Sar302503, N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide

2.4 Create Date

2007-09-03

3 Chemical and Physical Properties

Molecular Formula	C₂₇H₃₆N₆O₃S
Molecular Weight	524.7 g/mol
XLogP3	4.8
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	11
Exact Mass	524.25696021 g/mol
Monoisotopic Mass	524.25696021 g/mol
Topological Polar Surface Area	117 Å²
Heavy Atom Count	37
Formal Charge	0
Complexity	787
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Fedratinib is indicated to treat adults with primary or secondary myelofibrosis that is either intermediate-2 or high risk.

Inrebic is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor nave or have been treated with ruxolitinib.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Fedratinib is a kinase inhibitor that inhibits cell division and induces apoptosis. Patients taking fedratinib may experience anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, or elevated amylase and lipase. These effects should be managed by reducing the dose, temporarily stopping the medication, or providing transfusions on a case by case basis.

5.2 ATC Code

L01EJ02

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EJ - Janus-associated kinase (jak) inhibitors

L01EJ02 - Fedratinib

5.3 Absorption, Distribution and Excretion

Absorption

A 400mg oral dose results in a C_max of 1804ng/mL and an AUC of 26,870ng/*hr/mL. Fedratinib has a T_max of 1.75-3 hours. A high fat breakfast does not significantly affect the absorption of fedratinib.

Route of Elimination

An oral dose of fedratinib is 77% eliminated in the feces with 23% as unchanged drug. 5% is eliminated in the urine, with 3% as unchanged drug.

Volume of Distribution

The apparent volume of distribution is 1770L.

Clearance

The clearance of fedratinib is 13L/h.

5.4 Metabolism/Metabolites

Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3. Beyond that, data regarding the metabolism of fedratinib is not readily available.

5.5 Biological Half-Life

The half life of fedratinib is 41 hours with a terminal half life of 114 hours.

5.6 Mechanism of Action

Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3. JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis. Fedratinib's inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis.