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Brigatinib

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TABLET;ORAL - 180MG, TABLET;ORAL - 30MG, TABLET;ORAL - 90MG

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TABLET;ORAL - 30MG
TABLET;ORAL - 90MG

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Synopsis

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Chemistry

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Also known as: 1197953-54-0, Alunbrig, Ap-26113, Brigatinib [usan], Brigatinib (ap-26113), Hyw8db273j

Molecular Formula

C₂₉H₃₉ClN₇O₂P

Molecular Weight

584.1 g/mol

InChI Key

AILRADAXUVEEIR-UHFFFAOYSA-N

FDA UNII

HYW8DB273J

Brigatinib is an orally available inhibitor of receptor tyrosine kinases anaplastic lymphoma kinase (ALK) and the epidermal growth factor receptor (EGFR) with potential antineoplastic activity. Brigatinib binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. In addition, AP26113 appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. EGFR is overexpressed in a variety of cancer cell types.

Brigatinib is a Kinase Inhibitor. The mechanism of action of brigatinib is as a Tyrosine Kinase Inhibitor, and Cytochrome P450 3A Inducer.

1 2D Structure

Brigatinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine

2.1.2 InChI

InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)

2.1.3 InChI Key

AILRADAXUVEEIR-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC

2.2 Other Identifiers

2.2.1 UNII

HYW8DB273J

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Alunbrig

2. Ap26113

2.3.2 Depositor-Supplied Synonyms

1. 1197953-54-0

2. Alunbrig

3. Ap-26113

4. Brigatinib [usan]

5. Brigatinib (ap-26113)

6. Hyw8db273j

7. Ap 26113

8. (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine Oxide

9. 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine

10. 2,4-pyrimidinediamine, 5-chloro-n4-(2-(dimethylphosphinyl)phenyl)-n2-(2-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)-

11. 5-chloro-n4-(2-(dimethylphosphoryl)phenyl)-n2-(2-methoxy-4-(4-(4-methylpiperazin-1- Yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

12. 2,4-pyrimidinediamine, 5-chloro-n4-[2-(dimethylphosphinyl)phenyl]-n2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-

13. 5-chloro-n~4~-[2-(dimethylphosphoryl)phenyl]-n~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

14. Unii-hyw8db273j

15. Brigatiib

16. Alunbrig (tn)

17. 5-chloro-n4-(2-(dimethylphosphoryl)phenyl)-n2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

18. 5-chloro-n4-[2-(dimethylphosphoryl)phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

19. 6gy

20. Brigatinib [mi]

21. Brigatinib [inn]

22. Brigatinib [jan]

23. Brigatinib (jan/usan)

24. Brigatinib [usan:inn]

25. Brigatinib; Ap26113

26. Brigatinib (ap26113)

27. Brigatinib [who-dd]

28. 5-chloro-n4-[2-(dimethylphosphinyl)phenyl]-n2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidinediamine

29. Gtpl7741

30. Brigatinib [orange Book]

31. Chembl3545311

32. Schembl11916361

33. Ex-a775

34. Dtxsid501027929

35. Amy10294

36. Bcp17214

37. Bdbm50185140

38. Mfcd29472221

39. Nsc784728

40. Nsc787457

41. Akos030257612

42. Zinc148723177

43. Cs-4278

44. Db12267

45. Nsc-784728

46. Nsc-787457

47. Sb40412

48. Compound 11q [pmid: 27144831]

49. Ncgc00483924-01

50. (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl-,delta5-phosphanone

51. Ac-29958

52. As-75176

53. Hy-12857

54. Db-118419

55. Ft-0700112

56. S8229

57. J3.535.964h

58. D10866

59. Q27456393

60. (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl-,.delta.5-phosphanone

2.4 Create Date

2012-11-30

3 Chemical and Physical Properties

Molecular Formula	C₂₉H₃₉ClN₇O₂P
Molecular Weight	584.1 g/mol
XLogP3	4.6
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	8
Exact Mass	583.2591382 g/mol
Monoisotopic Mass	583.2591382 g/mol
Topological Polar Surface Area	85.9 Å²
Heavy Atom Count	40
Formal Charge	0
Complexity	835
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	ALUNBRIG
Active Ingredient	BRIGATINIB
Company	ARIAD (Application Number: N208772. Patents: 9012462, 9273077, 9611283)

4.2 Drug Indication

The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib.

FDA Label

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)positive advanced nonsmall cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase ALKpositive advanced NSCLC previously treated with crizotinib.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still unknown.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

BRIGATINIB

5.2.2 FDA UNII

HYW8DB273J

5.2.3 Pharmacological Classes

Kinase Inhibitor [EPC]; Tyrosine Kinase Inhibitors [MoA]; Cytochrome P450 3A Inducers [MoA]

5.3 ATC Code

L01XE43

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01ED - Anaplastic lymphoma kinase (alk) inhibitors

L01ED04 - Brigatinib

5.4 Absorption, Distribution and Excretion

Absorption

Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC.

Route of Elimination

The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine.

Volume of Distribution

The apparent volume of distribution at steady state is 153 L.

Clearance

After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h.

5.5 Metabolism/Metabolites

Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower.

5.6 Biological Half-Life

The half-life of brigatinib at steady-state was 25 hours.

5.7 Mechanism of Action

Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins.

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