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Also known as: 1110813-31-4, Pf-00299804, Pf299804, Dacomitinib (pf299804, pf299), Dacomitinib anhydrous, (2e)-n-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide
Molecular Formula
C24H25ClFN5O2
Molecular Weight
469.9  g/mol
InChI Key
LVXJQMNHJWSHET-AATRIKPKSA-N
FDA UNII
2XJX250C20

Dacomitinib
Dacomitinib, designed as (2E)-N-16-4-(piperidin-1-yl) but-2-enamide, is an oral highly selective quinazalone part of the second-generation tyrosine kinase inhibitors which are characterized by the irreversible binding at the ATP domain of the epidermal growth factor receptor family kinase domains. Dacomitinib was developed by Pfizer Inc and approved by the FDA on September 27, 2018. Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer model, although further investigations are needed.
1 2D Structure

Dacomitinib

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide
2.1.2 InChI
InChI=1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+
2.1.3 InChI Key
LVXJQMNHJWSHET-AATRIKPKSA-N
2.1.4 Canonical SMILES
COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)C=CCN4CCCCC4
2.1.5 Isomeric SMILES
COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)/C=C/CN4CCCCC4
2.2 Other Identifiers
2.2.1 UNII
2XJX250C20
2.3 Synonyms
2.3.1 MeSH Synonyms

1. N-(4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-2-butenamide

2. Pf 00299804

3. Pf-00299804

4. Pf00299804

5. Vizimpro

2.3.2 Depositor-Supplied Synonyms

1. 1110813-31-4

2. Pf-00299804

3. Pf299804

4. Dacomitinib (pf299804, Pf299)

5. Dacomitinib Anhydrous

6. (2e)-n-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide

7. (e)-n-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide

8. Pf-299804

9. Dacomitinib (pf299804)

10. 2xjx250c20

11. Pf 00299804-03

12. Dacomitinib (inn)

13. Dacomitinib [inn]

14. (e)-n-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide

15. (2e)-n-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide

16. Dacomitinib [usan:inn]

17. Dacomitinibum

18. Unii-2xjx250c20

19. Pf299

20. (e)-n-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)but-2-enamide

21. Pf-299

22. Dacomitinib [who-dd]

23. Mls006011275

24. Gtpl7422

25. Chembl2110732

26. Chebi:91466

27. Dtxsid50149493

28. Ex-a030

29. Chebi:132268

30. Bdbm112499

31. Dacomitinib (pf-00299804)

32. Amy21292

33. Bcp02530

34. Mfcd19443734

35. Nsc765888

36. Nsc800084

37. S2727

38. Zinc72266312

39. Akos025401818

40. Ccg-264987

41. Cs-0500

42. Db11963

43. Nsc-765888

44. Nsc-800084

45. Us8623883, No. 2

46. Ncgc00263185-09

47. Ncgc00263185-10

48. Ac-25915

49. As-57686

50. Hy-13272

51. Smr004703025

52. D5450

53. Sw219155-1

54. D09883

55. Dacomitinib (pf299804, Pf-00299804)

56. Pf-299804 (dacomitinib Pf-00299804)

57. J-500784

58. Q17130597

59. (2e)-n-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-piperidin-1-ylbut-2-enamide

60. (2e)-n-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)but-2-enamide

61. (e)-n-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide

62. (e)-n-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide

63. 2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-, (2e)-

2.4 Create Date
2006-10-26
3 Chemical and Physical Properties
Molecular Weight 469.9 g/mol
Molecular Formula C24H25ClFN5O2
XLogP34.4
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count7
Rotatable Bond Count7
Exact Mass469.1680809 g/mol
Monoisotopic Mass469.1680809 g/mol
Topological Polar Surface Area79.4 Ų
Heavy Atom Count33
Formal Charge0
Complexity665
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count1
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

Dacomitinib is indicated as the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as verified by an FDA-approved test. Lung cancer is the leading cause of cancer death and NSCLC accounts for 85% of lung cancer cases. From the cases of NSCLC, approximately 75% of the patients present a late diagnosis with metastatic and advanced disease which produces a survival rate of 5%. The presence of a mutation in EGFR accounts for more than the 60% of the NSCLC cases and the overexpression of EGFR is associated with frequent lymph node metastasis and poor chemosensitivity.


FDA Label


Vizimpro, as monotherapy, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Preclinical data suggested that dacomitinib increases the inhibition of the epidermal growth factor receptor kinase domain as well as the activity in cell lines harboring resistance mutations such as T790M. This activity further produced a significant reduction of EGFR phosphorylation and cell viability. In these studies, non-small cell lymphoma cancer cell lines with L858R/T790M mutations where used and an IC50 of about 280 nmol/L was observed. In clinical trials with patients with advanced non-small cell lung carcinoma who progressed after chemotherapy, there was an objective response rate of 5% with a progression-free survival of 2.8 months and an overall survival of 9.5 months. As well, phase I/II studies showed positive dacomitinib activity despite prior failure with tyrosine kinase inhibitors. Phase III clinical trials (ARCHER 1050), done in patients suffering from advanced or metastatic non-small cell lung carcinoma with EGFR-activating mutations, reported a significant improvement in progression-free survival when compared with gefitinib.


5.2 ATC Code

L01EB07


L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EB - Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors

L01EB07 - Dacomitinib


5.3 Absorption, Distribution and Excretion

Absorption

Dacomitinib has shown a linear kinetics after single and multiple dose range studies. The absorption and distribution do not seem to be affected by food or the consumption of antacids. The peak plasma concentration after a dosage of 45 mg for 4 days is of 104 ng/ml. The reported AUC0-24h and tmax are of 2213 ng.h/mL and 6 hours, respectively. As well, following oral administration, the absolute oral bioavailability is 80%.


Route of Elimination

From the administered dose, 79% is recovered in feces, from which 20% represents the unmodified form of dacomitinib, and 3% is recovered in urine, from which <1% is represented by the unchanged form.


Volume of Distribution

The volume of distribution of dacomitinib was reported to be of 2415 L.


Clearance

The geometric apparent clearance of dacomitinib is 27.06 L/h.


5.4 Metabolism/Metabolites

Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes. After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265. This metabolite has been shown to be formed by an oxidative step by CYP2D6 and to a smaller extent by CYP2C9. The following steps of the metabolism are mainly mediated by CYP3A4 for the formation of smaller metabolites. From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6.


5.5 Biological Half-Life

Dacomitinib is reported to have a very large half-life of 70 hours.


5.6 Mechanism of Action

Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus. Around 40% of cases show amplification of EGFR gene and 50% of the cases present the _EGFRvIII_ mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor.


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Antibody Engineering
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Company :

Dacomitinib

Drug Cost (USD) : 2,379,396

Year : 2022

Prescribers : 30

Prescriptions : 150

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02

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Company :

Dacomitinib

Drug Cost (USD) : 2,472,649

Year : 2021

Prescribers : 38

Prescriptions : 170

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03

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Company :

Dacomitinib

Drug Cost (USD) : 2,064,000

Year : 2019

Prescribers : 37

Prescriptions : 150

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Company :

Dacomitinib

Drug Cost (USD) : 0

Year : 2018

Prescribers :

Prescriptions : 0

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Dacomitinib

Drug Cost (USD) : 0

Year : 2017

Prescribers :

Prescriptions : 0

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06

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Dacomitinib

Drug Cost (USD) : 0

Year : 2016

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Prescriptions : 0

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Company :

Dacomitinib

Drug Cost (USD) : 0

Year : 2015

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Prescriptions : 0

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