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Infigratinib

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8 US Patents, 4 US Exclusivities

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8 US Patents
4 US Exclusivities

Synopsis

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Chemistry

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Also known as: Nvp-bgj398, 872511-34-7, Bgj398, Bgj-398, Bgj 398, Truseltiq

Molecular Formula

C₂₆H₃₁Cl₂N₇O₃

Molecular Weight

560.5 g/mol

InChI Key

QADPYRIHXKWUSV-UHFFFAOYSA-N

FDA UNII

A4055ME1VK

Infigratinib is an orally bioavailable pan inhibitor of human fibroblast growth factor receptors (FGFRs) with potential antiangiogenic and antineoplastic activities. Infigratinib selectively binds to and inhibits the activities of FGFRs, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. FGFRs are a family of receptor tyrosine kinases which may be upregulated in various tumor cell types and may be involved in tumor cell differentiation and proliferation, tumor angiogenesis, and tumor cell survival.

1 2D Structure

Infigratinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea

2.1.2 InChI

InChI=1S/C26H31Cl2N7O3/c1-5-34-10-12-35(13-11-34)18-8-6-17(7-9-18)31-21-15-22(30-16-29-21)33(2)26(36)32-25-23(27)19(37-3)14-20(38-4)24(25)28/h6-9,14-16H,5,10-13H2,1-4H3,(H,32,36)(H,29,30,31)

2.1.3 InChI Key

QADPYRIHXKWUSV-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl

2.2 Other Identifiers

2.2.1 UNII

A4055ME1VK

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea

2. Bgj398

3. Nvp-bgj398

4. Truseltiq

2.3.2 Depositor-Supplied Synonyms

1. Nvp-bgj398

2. 872511-34-7

3. Bgj398

4. Bgj-398

5. Bgj 398

6. Truseltiq

7. Infigratinib [inn]

8. Infigratinib Free Base

9. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea

10. Infigratinib [usan]

11. Bgj398 (nvp-bgj398)

12. Mvp-bgj398

13. A4055me1vk

14. Chebi:63451

15. 872511-34-7 (free Base)

16. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methylurea

17. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea

18. Urea, N'-(2,6-dichloro-3,5-dimethoxyphenyl)-n-(6-((4-(4-ethyl-1-piperazinyl)phenyl)amino)-4-pyrimidinyl)-n-methyl-

19. Chembl1834657

20. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea.

21. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[[4-(4-ethylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]-1-methylurea

22. Unii-a4055me1vk

23. Infigratinib (bgj398)

24. Infigratinib (usan/inn)

25. Infigratinib [usan:inn]

26. Nvp-bgj389

27. Nvp-bgj398(infigratinib)

28. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)-1-methylurea

29. Mls006010953

30. Infigratinib [who-dd]

31. Schembl374435

32. Gtpl7877

33. Chembl1852688

34. Dtxsid70236238

35. Ex-a057

36. Bgj398, Bgj-398

37. Hms3295o21

38. Amy10737

39. Bcp03602

40. Bgj398 - Nvp-bgj398

41. Bdbm50355393

42. Fd5035

43. Mfcd22123241

44. Nsc764487

45. S2183

46. Who 10032

47. Zinc72105034

48. Akos025149513

49. Akos032949944

50. Bcp9000399

51. Cs-0586

52. Db11886

53. Nsc-764487

54. Sb16612

55. Ncgc00274030-01

56. Ncgc00274030-11

57. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea

58. Ac-28417

59. As-16290

60. Hy-13311

61. Smr004702757

62. Bcp0726000187

63. Ft-0699366

64. D11589

65. J-510477

66. Brd-k42728290-001-01-8

67. Q27075200

68. 07j

69. 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

70. N'-(2,6-dichloro-3,5-dimethoxyphenyl)-n-(6-((4-(4-ethyl-1- Piperazinyl)phenyl)amino)-4-pyrimidinyl)-n-methylurea

2.4 Create Date

2011-07-05

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₃₁Cl₂N₇O₃
Molecular Weight	560.5 g/mol
XLogP3	4.7
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	8
Exact Mass	559.1865433 g/mol
Monoisotopic Mass	559.1865433 g/mol
Topological Polar Surface Area	95.1 Å²
Heavy Atom Count	38
Formal Charge	0
Complexity	724
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

Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.

Treatment of cholangiocarcinoma

Treatment of achondroplasia

5 Pharmacology and Biochemistry

5.1 Pharmacology

Infigratinib is an anti-tumour agent that works to suppress tumour growth in cholangiocarcinoma. It exhibits anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR2 or FGFR3 alterations, such as FGFR2-TTC28 or FGFR2-TRA2B fusions. In clinical trials, patients with cholangiocarcinoma who were treated with infigratinib had an overall response rate of 23% - where one patient had a complete response - and a duration of response of 5.5 months, with a range between 0.03 and 28.3 months. Some patients with cancers with FGFR mutations display intrinsic resistance to infigratinib, leading to negligible therapeutic efficacy: investigations are ongoing to target molecular pathways to combat drug resistance.

5.2 MeSH Pharmacological Classification

Antineoplastic Agents

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

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EN - Fibroblast growth factor receptor (fgfr) tyrosine kinase inhibitors

L01EN03 - Infigratinib

5.4 Absorption, Distribution and Excretion

Absorption

Mean (%CV) C_max is 282.5 ng/mL (54%) and AUC_0-24h is 3780 ngxh/mL (59%) for infigratinib. Infigratinib C_max and AUC increase more than proportionally across the dose range of 5 to 150 mg and steady state is achieved within 15 days. At steady state, median time to achieve peak infigratinib plasma concentration (T_max) is six hours, with a range between two and seven hours. Mean (%CV) C_max is 42.1 ng/mL (65%) for BHS697 and 15.7 ng/mL (92%) for CQM157. Mean (%CV) AUC_0-24h is 717 ngxh/mL (55%) for BHS697 and 428 ngxh/mL (72%) for CQM157. In healthy subjects, a high-fat and high-calorie meal increased AUCinf of infigratinib by 80%-120% and C_max by 60%-80%. The median T_max also shifted from four hours to six hours. A low-fat low-calorie meal increased the mean AUC_inf of infigratinib by 70% and C_max by 90%/

Route of Elimination

Following administration of a single oral dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces, where 3.4% of the dose was in the unchanged parent form. About 7.2% was recovered in urine with 1.9% of the dose was unchanged.

Volume of Distribution

At steady state, the geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%). In rats receiving a single oral dose, infigratinib had brain-to-plasma concentration ratios (based on AUC_0-inf) of 0.682.

Clearance

The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) at steady state.

5.5 Metabolism/Metabolites

According to _in vitro_ findings, about 94% of infigratinib is metabolized by CYP3A4 and about 6% of the drug is metabolized by flavin-containing monooxygenase 3 (FMO3). About 38% of the dose is circulating parent drug in the plasma and BHS697 and CQM157 are two major metabolites of infigratinib that are each found at >10% of the dose. They are pharmacologically active, with BHS697 representing about 16% to 33% of the overall pharmacological activity of infigratinib and CQM157 contributing to about 9% to 12%. BHS697 undergoes further metabolism mediated by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways. The exact metabolic pathways and the structure of BHS697 and CQM157 are not fully characterized.

5.6 Biological Half-Life

The geometric mean (CV%) terminal half-life of infigratinib was 33.5 h (39%) at steady state.

5.7 Mechanism of Action

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that play a role in cell proliferation, differentiation, migration, survival, and angiogenesis. Upon binding of extracellular signals, primarily fibroblast growth factors, FGFR dimerizes to promote phosphorylation of downstream molecules and activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. In some cancers, the FGFR signalling pathway is aberrant and disrupted, leading to unregulated cell proliferation and growth, including malignant cells. Alterations in the FGFR receptors, including mutations, amplifications, and fusions, are associated with a wide array of neoplasms, including prostate, urothelial, ovarian, breast, and liver cancer. In particular, FGFR2 fusion is closely related to intrahepatic cholangiocarcinoma: recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in FGFR2 fusion proteins. Alterations in FGFR in tumours can lead to constitutive FGFR signalling, supporting the proliferation and survival of malignant cells. Infigratinib is a reversible, non-competitive inhibitor of all four FGFR subtypes - FGFR1, FGFR2, FGFR3, and FGFR4 - that blocks FGFR signalling and inhibits cell proliferation in cancer cell lines with activating FGFR amplification, mutations, or fusions. Out of the four FGFR subtypes, infigratinib has the highest affinity for FGFR1, FGFR2, and FGFR3. Infigratinib binds to the allosteric site between the two kinase lobes of the FGFR - or more specifically, to the ATP-binding cleft. Binding to this cleft prevents autophosphorylation of the receptor and blocks downstream signalling cascades that would otherwise activate MAPK.

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