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Ivosidenib

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31 US Patents, 7 US Exclusivities

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Chemistry

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Also known as: 1448347-49-6, Tibsovo, Ag-120, Ag120, Ivosidenib [inn], Ivosidenib [usan]

Molecular Formula

C₂₈H₂₂ClF₃N₆O₃

Molecular Weight

583.0 g/mol

InChI Key

WIJZXSAJMHAVGX-DHLKQENFSA-N

FDA UNII

Q2PCN8MAM6

Ivosidenib is an orally available inhibitor of isocitrate dehydrogenase type 1 (IDH1), with potential antineoplastic activity. Upon administration, AG-120 specifically inhibits a mutated form of IDH1 in the cytoplasm, which inhibits the formation of the oncometabolite, 2-hydroxyglutarate (2HG). This may lead to both an induction of cellular differentiation and an inhibition of cellular proliferation in IDH1-expressing tumor cells. IDH1, an enzyme in the citric acid cycle, is mutated in a variety of cancers; it initiates and drives cancer growth by both blocking cell differentiation and catalyzing the formation of 2HG.

1 2D Structure

Ivosidenib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

2.1.2 InChI

InChI=1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25-/m0/s1

2.1.3 InChI Key

WIJZXSAJMHAVGX-DHLKQENFSA-N

2.1.4 Canonical SMILES

C1CC(=O)N(C1C(=O)N(C2=CC(=CN=C2)F)C(C3=CC=CC=C3Cl)C(=O)NC4CC(C4)(F)F)C5=NC=CC(=C5)C#N

2.1.5 Isomeric SMILES

C1CC(=O)N([C@@H]1C(=O)N(C2=CC(=CN=C2)F)[C@@H](C3=CC=CC=C3Cl)C(=O)NC4CC(C4)(F)F)C5=NC=CC(=C5)C#N

2.2 Other Identifiers

2.2.1 UNII

Q2PCN8MAM6

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Ag-120

2. Ag120

3. N-((1s)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyano-2-pyridinyl)-n-(5-fluoro-3-pyridinyl)-5-oxo-l-prolinamide

4. Tibsovo

2.3.2 Depositor-Supplied Synonyms

1. 1448347-49-6

2. Tibsovo

3. Ag-120

4. Ag120

5. Ivosidenib [inn]

6. Ivosidenib [usan]

7. Ivosidenib [who-dd]

8. Q2pcn8mam6

9. (2s)-n-[(1s)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

10. (s)-n-((s)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

11. Glycinamide, 1-(4-cyano-2-pyridinyl)-5-oxo-l-prolyl-2-(2-chlorophenyl)-n-(3,3-difluorocyclobutyl)-n2-(5-fluoro-3-pyridinyl)-, (2s)-

12. Rg120

13. Ivosidenibum

14. (2s)-n-((1s)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

15. (2s)-n-{(1s)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

16. Tibsovo (tn)

17. Ivosidenib [mi]

18. Ivosidenib (usan/inn)

19. Ivosidenib [usan:inn]

20. Unii-q2pcn8mam6

21. Gtpl9217

22. Chembl3989958

23. Ivosidenib [orange Book]

24. Schembl15122512

25. Ex-a992

26. Chebi:145430

27. Bdbm363689

28. Dtxsid801027928

29. Amy38924

30. Us9850277, Compound 176

31. Mfcd29036964

32. Nsc789102

33. S8206

34. Zinc205136523

35. Ccg-270141

36. Cs-5122

37. Db14568

38. Nsc-789102

39. Ncgc00476170-04

40. Ncgc00476170-06

41. (s)-n-((s)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-n-

42. (s)-n-((s)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

43. Ac-32624

44. As-35058

45. Hy-18767

46. A14386

47. D11090

48. A900315

49. Q27895417

50. (2s)-1-(4-cyano-2-pyridinyl)-5-oxo-l-prolyl-2-(2-chloroph)-n-(3,3-difluorocyclobutyl)-n2-(5-fluoro-3-pyridinyl)-glycinamide

51. (s)-n-((s)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide;ag-120

52. N-{(1s)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxo-l-prolinamide

2.4 Create Date

2013-08-19

3 Chemical and Physical Properties

Molecular Formula	C₂₈H₂₂ClF₃N₆O₃
Molecular Weight	583.0 g/mol
XLogP3	3.4
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	7
Exact Mass	582.1394008 g/mol
Monoisotopic Mass	582.1394008 g/mol
Topological Polar Surface Area	119 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	1050
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
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

Ivosidenib is approved for use in the treatment of relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test.

FDA Label

Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms), Treatment of malignant neoplasms of the central nervous system

Treatment of acute myeloid leukaemia

5 Pharmacology and Biochemistry

5.1 Pharmacology

Many cancers undergo missense mutations of their IDH1 gene leading to substitution of arginine 132 residue of the IDH1 enzyme [A35629. This substitution leads to reduced production of the normal carboxylic acid cycle metabolite -ketoglutarate (-KG) in favor of a new metabolite, D-2-hydroxyglutarate (D-2HG) which reaches levels of 50-100 fold that of wild type cells. D-2HG is a weak competitor to -KG, inhibiting aKG-dependent dioxygenases, and is present . These dioxygenases include several histone demethylases. This leads to hypermethylation of histones, a dominant feature of AML, which is associated with less expression of cell-differentiation genes. Furthermore, methylation sensitive insulators can no longer regulate the activation of oncogenes when histones are hypermethylated. In AML this hypermethylation is known to disrupt hematopoietic differentiation. Ivosidenib reduces the production of D-2HG, relieving the inhibition of histone demethylases and restoring normal methylation conditions. This restores cell differentiation and oncogene regulation leading to regression of the cancer.

5.2 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Enzyme Inhibitors

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XX - Other antineoplastic agents

L01XX62 - Ivosidenib

5.4 Absorption, Distribution and Excretion

Absorption

Ivosidenib has a Tmax of 3 hours following oral administration of a 2 250 mg tablets (total 500 mg). When given with a high-fat meal, Cmax increases by 98% and AUC by 25%. The AUC and Cmax increase in a less than dose-proportional manner in the range of 200-1200 mg daily. Accumulation ratios have been determined to be 1.9 for AUC and 1.5 for Cmax over the course of one month. Steady state is known to be reached within 14 days of daily administration.

Route of Elimination

Following oral administration, 77% of Ivosidenib is eliminated in the feces with 67% present as the parent drug. 17% is excreted in the urine with 10% as the parent drug. No clinically meaningful effects on elimination have been observed with mild to moderate renal impairment or mild hepatic impairment. Changes in patients with severe renal impairment or moderate too severe hepatic impairment have not been investigated.

Volume of Distribution

Ivosidenib has a mean apparent Vd of 234 L at steady-state.

Clearance

Ivosidenib has an apparent clearance rate of 4.3 L/h

5.5 Metabolism/Metabolites

Over 92% of Ivosidenib is present in circulation as the parent drug. Metabolism occurs primarily through CYP3A4 with some contribution from N-dealkylation and hydrolysis.

5.6 Biological Half-Life

Ivosidenib has a terminal half-life of 93 h.

5.7 Mechanism of Action

Ivosidenib is a reversible inhibitor of IDH1 which is non-competitive with respect to the cofactor NADH. It binds to many different 132-substituted IDH1 mutants as well as the wild type enzyme. It is considered to be a slow-binder of the wild type enzyme and binds to mutant enzymes at lower concentrations, both of which may contribute its selectivity. Ivosidenib has not been observed to inhibit any form of IDH2 at micromolar concentrations.

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