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Pemigatinib

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Also known as: 1513857-77-6, Pemazyre, Incb054828, Pemigatinib [inn], Fgfr inhibitor incb054828, Pemigatinib [usan]

Molecular Formula

C₂₄H₂₇F₂N₅O₄

Molecular Weight

487.5 g/mol

InChI Key

HCDMJFOHIXMBOV-UHFFFAOYSA-N

FDA UNII

Y6BX7BL23K

Pemigatinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. Pemigatinib binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells. FGFR, a family of receptor tyrosine kinases upregulated in many tumor cell types, plays a key role in cellular proliferation, migration, and survival.

Pemigatinib is a Kinase Inhibitor. The mechanism of action of pemigatinib is as a Kinase Inhibitor, and P-Glycoprotein Inhibitor, and Organic Cation Transporter 2 Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor.

1 2D Structure

Pemigatinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

11-(2,6-difluoro-3,5-dimethoxyphenyl)-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1,3,6,8-tetraen-12-one

2.1.2 InChI

InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)

2.1.3 InChI Key

HCDMJFOHIXMBOV-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CCN1C2=C3C=C(NC3=NC=C2CN(C1=O)C4=C(C(=CC(=C4F)OC)OC)F)CN5CCOCC5

2.2 Other Identifiers

2.2.1 UNII

Y6BX7BL23K

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 2h-pyrrolo(3',2':5,6)pyrido(4,3-d)pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-

2. Incb-054828

3. Incb054828

4. Pemazyre

2.3.2 Depositor-Supplied Synonyms

1. 1513857-77-6

2. Pemazyre

3. Incb054828

4. Pemigatinib [inn]

5. Fgfr Inhibitor Incb054828

6. Pemigatinib [usan]

7. Incb-054828

8. Y6bx7bl23k

9. Incb54828

10. Incb-54828

11. 1513857-77-6 (free Base)

12. 2h-pyrrolo(3',2':5,6)pyrido(4,3-d)pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-

13. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,6-tetrahydro-2h-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one

14. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(morpholin-4-yl)methyl]-1,3,4,7-tetrahydro-2hpyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one

15. Pemazyre (tn)

16. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2h-pyrrolo(3',2':5,6)pyrido(4,3-d)pyrimidin-2-one

17. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2h-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one

18. Pemigatinib [mi]

19. Pemigatinib [jan]

20. Pemigatinib [usan:inn]

21. Unii-y6bx7bl23k

22. Pemigatinib [who-dd]

23. Pemigatinib (jan/usan/inn)

24. Gtpl9767

25. Pemigatinib (incb054828)

26. Chembl4297522

27. Schembl15556271

28. Pemigatinib [orange Book]

29. Bdbm301310

30. Dtxsid501027955

31. Incb 54828

32. Ex-a4049

33. Nsc816556

34. Us10131667, Example 126

35. At15587

36. Db15102

37. Incb054828incb054828

38. Nsc-816556

39. Ac-36489

40. As-78489

41. Example 126 [wo2014007951]

42. Hy-109099

43. Cs-0039499

44. D11417

45. A936247

46. 11-(2,6-difluoro-3,5-dimethoxyphenyl)-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1,3,6,8-tetraen-12-one

47. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2h-pyrrolo[3'',2'':5,6]pyrido[4,3-d]pyrimidin-2-one

48. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one

49. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-3,4-dihydro-1h-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2(7h)-one

2.4 Create Date

2015-02-02

3 Chemical and Physical Properties

Molecular Formula	C₂₄H₂₇F₂N₅O₄
Molecular Weight	487.5 g/mol
XLogP3	1.8
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	6
Exact Mass	487.20311068 g/mol
Monoisotopic Mass	487.20311068 g/mol
Topological Polar Surface Area	83.2 Å²
Heavy Atom Count	35
Formal Charge	0
Complexity	731
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

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

Pemazyre monotherapy is indicated for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Pemigatinib is a small molecule kinase inhibitor that exerts anti-tumour activity through inhibition of fibroblast growth factor receptors (FGFRs). With an IC₅₀ of less than 2 nM, pemigatinib displays potent inhibition of FGFR1, FGFR2, and FGFR3. In mouse xenograft models of human tumours with FGFR1, FGFR2, or FGFR3 alterations, pemigatinib exhibited potent anti-tumour activity by suppressing the growth of xenografted tumour models. It also showed efficacy against a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2 Transformer-2 beta homolog (TRA2b) fusion protein. Pemigatinib also inhibited FGFR4 _in vitro_, however at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

PEMIGATINIB

5.2.2 FDA UNII

Y6BX7BL23K

5.2.3 Pharmacological Classes

Kinase Inhibitors [MoA]; Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA]; Organic Cation Transporter 2 Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L01EX20

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

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

L01EN02 - Pemigatinib

5.4 Absorption, Distribution and Excretion

Absorption

Following administration of a single oral dose of 13.5 mg pemigatinib, the median Tmax was 1.13 (0.50-6.00) hours. The steady state was reached within 4 days following repeated once daily dosing, with the median drug accumulation ratio of 1.63 (range 0.63 to 3.28). Steady-state concentration of pemigatinib increased in a dose-proportional manner over the dose range of 1 to 20 mg, which is about 0.07 to 1.5 times the recommended dose. The mean steady-state AUC and Cmax were 2620 nM x h (54% CV) and 236 nM, respectively.

Route of Elimination

Following oral administration of a single radiolabeled dose of 11 mg pemigatinib, about 82.4% of the dose was recovered in feces. Of this recovered drug, about 1.4% of the dose was unchanged parent compound. About 12.6% of the dose was recovered in urine, where 1% of the dose was unchanged.

Volume of Distribution

The apparent volume of distribution was 235 L (60.8% CV) following a single oral dose of 13.5 mg pemigatinib.

Clearance

Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV).

5.5 Metabolism/Metabolites

Pemigatinib is predominantly metabolized by the CYP3A4 enzyme _in vitro_. Its specific metabolic pathway and resulting metabolites have not yet been characterized.

5.6 Biological Half-Life

Following administration of a single oral dose of 13.5 mg pemigatinib, the geometric mean elimination half-life (t) of pemigatinib was 15.4 (51.6% CV) hours.

5.7 Mechanism of Action

Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase involved in activating signalling pathways that promote cell proliferation, survival, and migration, as well as growth arrest and cellular differentiation. The initiation of the FGFR signalling pathway requires the binding of its natural ligand, fibroblast growth factor (FGF). Once FGF binds to the extracellular ligand-binding domain of the receptor, FGFRs dimerize and autophosphorylate the tyrosine residue in the intracellular tyrosine-kinase domain, leading to the activation of the tyrosine kinase. Downstream cascades involve phosphorylation of multiple intracellular signalling proteins, such as phosphatidylinositol 3 kinase (PI3K)-AKT and RAS/mitogen-activated protein kinase (MAPK), and phospholipase C, which activates the protein kinase C pathway. FGFR-mediated pathway ultimately promotes cell growth, differentiation, survival, angiogenesis, and organogenesis, depending on cell type. Expressed in different isoforms in various tissues and cell lines, FGFRs are not constitutively active in normal cells. However, FGFR1, FGFR2, or FGFR3 alterations in certain tumours can lead to constitutive FGFR activation and aberrant FGFR signalling, supporting the proliferation and survival of malignant cells. Pemigatinib inhibits FGFR1, FGFR2, and FGFR3, blocking their signalling pathways and decreasing cell viability in cancer cell lines with activating FGFR amplification and fusions that resulted in constitutive activation of FGFR signalling. Genetic alterations in FGFR1, FGFR2, and FGFR3 (such as amplification, missense, or fusion mutations in the coding region) leading to constitutive activation of FGFR signalling pathways are observed in various tumours. However, alterations in FGFR genes are demonstrated in selected patients and do not always imply oncogene development. Therefore, it is imperative that fusion or rearrangement of FGFRs are demonstrated through tests prior to initiation of drug therapy.

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