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Enasidenib Mesylate

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Chemistry

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Also known as: 1446502-11-9, Ag-221, Ag-221 (enasidenib), Enasidenib [inn], Cc-90007 free base, Idhifa

Molecular Formula

C₁₉H₁₇F₆N₇O

Molecular Weight

473.4 g/mol

InChI Key

DYLUUSLLRIQKOE-UHFFFAOYSA-N

FDA UNII

3T1SS4E7AG

Enasidenib is an orally available inhibitor of specific mutant forms of the mitochondrial enzyme isocitrate dehydrogenase type 2 (IDH2), with potential antineoplastic activity. Upon administration, enasidenib specifically inhibits various mutant forms of IDH2, including the IDH2 variants R140Q, R172S, and R172K, which inhibits the formation of 2-hydroxyglutarate (2HG). This may lead to both an induction of cellular differentiation and an inhibition of cellular proliferation in IDH2-expressing tumor cells. IDH2, an enzyme in the citric acid cycle, is mutated in a variety of cancers; it initiates and drives cancer growth by blocking differentiation and the production of the oncometabolite 2HG.

Enasidenib is an Isocitrate Dehydrogenase 2 Inhibitor. The mechanism of action of enasidenib is as an Isocitrate Dehydrogenase 2 Inhibitor.

1 2D Structure

Enasidenib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol

2.1.2 InChI

InChI=1S/C19H17F6N7O/c1-17(2,33)9-27-15-30-14(11-4-3-5-12(29-11)18(20,21)22)31-16(32-15)28-10-6-7-26-13(8-10)19(23,24)25/h3-8,33H,9H2,1-2H3,(H2,26,27,28,30,31,32)

2.1.3 InChI Key

DYLUUSLLRIQKOE-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC(C)(CNC1=NC(=NC(=N1)C2=NC(=CC=C2)C(F)(F)F)NC3=CC(=NC=C3)C(F)(F)F)O

2.2 Other Identifiers

2.2.1 UNII

3T1SS4E7AG

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Ag-221

2. Idhifa

2.3.2 Depositor-Supplied Synonyms

1. 1446502-11-9

2. Ag-221

3. Ag-221 (enasidenib)

4. Enasidenib [inn]

5. Cc-90007 Free Base

6. Idhifa

7. Ag 221

8. 2-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

9. 3t1ss4e7ag

10. 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol

11. 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol

12. 2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol

13. 2-propanol, 2-methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-

14. 2-propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino]-1,3,5-triazin-2-yl]amino]-

15. Unii-3t1ss4e7ag

16. Enasidenibum

17. Ag221

18. 2-methyl-1-({4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl}amino)propan-2-ol

19. Ag-221(enasidenib)

20. Ag-221; Enasidenib

21. Enasidenib; Ag-221

22. Enasidenib [mi]

23. Enasidenib (usan/inn)

24. Enasidenib [usan:inn]

25. Enasidenib [usan]

26. Enasidenib [who-dd]

27. Gtpl8960

28. Ag 221 [who-dd]

29. Chembl3989908

30. Schembl15102202

31. Ex-a654

32. Chebi:145374

33. Dtxsid801027942

34. Hms3873d03

35. Amy38698

36. Bcp16041

37. Bdbm50503251

38. Mfcd29472245

39. Nsc788120

40. S8205

41. Akos026750439

42. Zinc222731806

43. Ccg-269476

44. Cs-5017

45. Db13874

46. Nsc-788120

47. Sb19193

48. Ncgc00479249-03

49. Ncgc00479249-05

50. Ac-31318

51. As-75164

52. Hy-18690

53. Ft-0700204

54. D10901

55. A857662

56. J-690181

57. Q27077182

58. B0084-470859

59. Ag-221; Ag 221; Ag221; Cc-90007; Cc 90007; Cc90007

60. 1802003-09-3

61. 69q

2.4 Create Date

2015-02-13

3 Chemical and Physical Properties

Molecular Formula	C₁₉H₁₇F₆N₇O
Molecular Weight	473.4 g/mol
XLogP3	3.5
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	6
Exact Mass	473.13987716 g/mol
Monoisotopic Mass	473.13987716 g/mol
Topological Polar Surface Area	109 Å²
Heavy Atom Count	33
Formal Charge	0
Complexity	635
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 Information

1 of 1
Drug Name	IDHIFA
Active Ingredient	ENASIDENIB MESYLATE
Company	CELGENE CORP (Application Number: N209606. Patents: 9512107, 9732062, 9738625)

4.2 Drug Indication

Indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation.

FDA Label

Treatment of acute myeloid leukaemia

5 Pharmacology and Biochemistry

5.1 Pharmacology

In a study involving adult patients with relapsed or refractory AML, overall response rate of 40.3% was achieved in enasidenib therapy which was associated with cellular differentiation and maturation, typically without evidence of aplasia. Enasidenib is not shown to cause QTc prolongation.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

ENASIDENIB

5.2.2 FDA UNII

3T1SS4E7AG

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Isocitrate Dehydrogenase 2 Inhibitors

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XX - Other antineoplastic agents

L01XX59 - Enasidenib

5.4 Absorption, Distribution and Excretion

Absorption

Following a single oral dose of 100mg enasidenib, the peak plasma concentration of 1.3 mcg/mL is reached at 4 hours after ingestion. The absolute bioavailability is aproximately 57% and the steady-state plasma levels are reached within 29 days of once-daily dosing.

Route of Elimination

Elimination of enasidenib involves 89% of fecal excretion and 11% of renal excretion. Unchanged drug accounts for 34% and 0.4% of the total drug detected in the feces and urine, respectively.

Volume of Distribution

The mean volume of distribution is 55.8L.

Clearance

Enasidenib displays a mean total body clearance (CL/F) of 0.74 L/hour.

5.5 Metabolism/Metabolites

Enasidenib undergoes N-dealkylation mediated by multiple CYP (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and UGT (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) enzymes to form AGI-16903, as suggested by in vitro studies. AGI-16903 can be further metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9. The parent drug accounts for 89% of total detectable drug in the circulation, while AGI-16903 represents 10% of circulating total drug.

5.6 Biological Half-Life

Enasidenib has a terminal half-life of 137 hours.

5.7 Mechanism of Action

Enasidenib is a selective inhibitor of IDH2, a mitochondria-localized enzyme involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. Wild-type IDH proteins play a cruicial role in the Krebs/citric acid cycle where it catalyzes the oxidative decarboxylation of isocitrate to -ketoglutarate. In comparison, mutant forms of IDH2 enzyme mediates a neomorphic activity and catalyze reduction of -KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked cellular differentiation of hematopoietic progenitor cells. Enasidenib primarily targets the mutant IDH2 variants R140Q, R172S, and R172K with higher potency than the wild type enzyme form. Inhibition of the enzyme leads to decreased levels of 2-hydroxyglutarate (2-HG) and promotion of proper differentiation and clonal proliferation of cells of the myeloid lineage.

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