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Chemistry

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Also known as: 1100598-32-0, Emd-1214063, Emd 1214063, Tepotinib [inn], Emd1214063, Msc2156119
Molecular Formula
C29H28N6O2
Molecular Weight
492.6  g/mol
InChI Key
AHYMHWXQRWRBKT-UHFFFAOYSA-N
FDA UNII
1IJV77EI07

Tepotinib
Tepotinib is an orally bioavailable inhibitor of MET tyrosine kinase with potential antineoplastic activity. Tepotinib selectively binds to MET tyrosine kinase and disrupts MET signal transduction pathways, which may induce apoptosis in tumor cells overexpressing this kinase. The receptor tyrosine kinase MET (also known as hepatocyte growth factor receptor or HGFR), is the product of the proto-oncogene c-Met and is overexpressed or mutated in many tumor cell types; this protein plays key roles in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis.
Tepotinib is a Kinase Inhibitor. The mechanism of action of tepotinib is as a Mesenchymal Epithelial Transition Inhibitor, and P-Glycoprotein Inhibitor.
1 2D Structure

Tepotinib

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile
2.1.2 InChI
InChI=1S/C29H28N6O2/c1-34-12-10-21(11-13-34)20-37-26-17-31-29(32-18-26)25-7-3-5-23(15-25)19-35-28(36)9-8-27(33-35)24-6-2-4-22(14-24)16-30/h2-9,14-15,17-18,21H,10-13,19-20H2,1H3
2.1.3 InChI Key
AHYMHWXQRWRBKT-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CN1CCC(CC1)COC2=CN=C(N=C2)C3=CC=CC(=C3)CN4C(=O)C=CC(=N4)C5=CC=CC(=C5)C#N
2.2 Other Identifiers
2.2.1 UNII
1IJV77EI07
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 3-(1-(3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)benzyl)-6-oxo-1,6-dihydro-3-pyridazinyl)benzonitrile

2. Benzonitrile, 3-(1,6-dihydro-1-((3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)phenyl)methyl)-6-oxo-3-pyridazinyl)-

3. Tepmetko

2.3.2 Depositor-Supplied Synonyms

1. 1100598-32-0

2. Emd-1214063

3. Emd 1214063

4. Tepotinib [inn]

5. Emd1214063

6. Msc2156119

7. Msc-2156119j

8. Tepmetko

9. Tepotinib [usan]

10. Msc-2156119

11. Msc2156119j

12. 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile

13. 1ijv77ei07

14. Tepotinib (emd 1214063)

15. 3-(1-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

16. Benzonitrile, 3-(1,6-dihydro-1-((3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)phenyl)methyl)-6-oxo-3-pyridazinyl)-

17. Benzonitrile, 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]-

18. 3-[1-(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile

19. Unii-1ijv77ei07

20. Tepotinib (usan/inn)

21. Tepotinib [who-dd]

22. Mls006010785

23. Gtpl8293

24. Schembl1296895

25. Tepotinib(emd-1214063)

26. Chembl3402762

27. Dtxsid70149132

28. Ex-a394

29. Who 9934

30. Bdbm50065457

31. Mfcd18452823

32. Nsc758244

33. Nsc781256

34. Nsc800945

35. S7067

36. Zinc43202335

37. Ccg-269632

38. Cs-0647

39. Db15133

40. Nsc-758244

41. Nsc-781256

42. Nsc-800945

43. Sb16609

44. Compound 22 [pmid: 25736998]

45. Ncgc00345793-01

46. Ncgc00345793-08

47. Ac-35185

48. As-16915

49. Hy-14721

50. Smr004701471

51. D11717

52. J-002366

53. Q27088961

54. 1100598-30-8

55. 3-(1-(3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)benzyl)-6-oxo-1,6-dihydro-3-pyridazinyl)benzonitrile

56. 3-(1-{3-[5-(1-methylpiperidin-4-yl-methoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

57. 3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

58. 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]benzonitrile

59. 3e8

2.4 Create Date
2009-03-03
3 Chemical and Physical Properties
Molecular Weight 492.6 g/mol
Molecular Formula C29H28N6O2
XLogP33.4
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count7
Rotatable Bond Count7
Exact Mass492.22737416 g/mol
Monoisotopic Mass492.22737416 g/mol
Topological Polar Surface Area94.7 Ų
Heavy Atom Count37
Formal Charge0
Complexity880
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

Tepotinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) who have mesenchymal-epithelial transition (_MET_) exon 14 skipping alterations.


Tepmetko as monotherapy is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harbouring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC50 of approximately 1.7 nmol/L. It has a moderate duration of action necessitating once-daily administration. Tepotinib has been associated with the development of interstitial lung disease (ILD)/pneumonitis, which can sometimes be fatal. Patients should be monitored closely for signs of new or worsening respiratory symptoms (e.g. dyspnea, cough), and treatment with tepotinib should be immediately withheld if ILD/pneumonitis is suspected. If no other potential causes of ILD/pneumonitis are identified, therapy with tepotinib should be suspended indefinitely.


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 FDA Pharmacological Classification
5.3.1 Active Moiety
TEPOTINIB
5.3.2 FDA UNII
1IJV77EI07
5.3.3 Pharmacological Classes
Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors
5.4 ATC Code

L01EX21


L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EX - Other protein kinase inhibitors

L01EX21 - Tepotinib


5.5 Absorption, Distribution and Excretion

Absorption

The absolute bioavailability of tepotinib following oral administration is approximately 72%. At the recommended dosage of 450mg once daily, the median Tmax is 8 hours and the mean steady-state Cmax and AUC0-24h were 1,291 ng/mL and 27,438 ngh/mL, respectively. Co-administration with a high-fat, high-calorie meal increases the AUC and Cmax of tepotinib by approximately 1.6-fold and 2-fold, respectively.


Route of Elimination

Following oral administration, approximately 85% of the given dose is excreted in the feces with the remainder excreted in the urine. Unchanged parent drug accounts for roughly half of the dose excreted in the feces, with the remainder comprising the demethylated M478 metabolite, a glucuronide metabolite, the racemic M506 metabolite, and some minor oxidative metabolites. Unchanged parent drug also accounts for roughly half of the dose excreted in the urine, with the remainder comprising a glucuronide metabolite and a pair of N-oxide diastereomer metabolites.


Volume of Distribution

The mean apparent volume of distribution is 1,038L.


Clearance

The apparent clearance of tepotinib is 23.8 L/h.


5.6 Metabolism/Metabolites

Tepotinib is metabolized primarily by CYP3A4 and CYP2C8, with some apparent contribution by unspecified UGT enzymes. The metabolite M506 is the major circulating metabolite, comprising approximately 40.4% of observed drug material in plasma, while the M668 glucuronide metabolite has been observed in plasma at much lower quantities (~4% of an orally administered dose). A total of 10 phase I and phase II metabolites have been detected following tepotinib administration, most of which are excreted in the feces.


5.7 Biological Half-Life

Following oral administration, the half-life of tepotinib is approximately 32 hours.


5.8 Mechanism of Action

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase found overexpressed and/or mutated in a variety of tumor types, thus making it a desirable target in their treatment. MET plays a critical role in the proliferation, survival, invasion, and mobilization of tumor cells, and aberrant MET activation is thought to contribute to the development of more aggressive cancers with poorer prognoses. Tepotinib is a kinase inhibitor directed against MET, including variants with exon 14 skipping - it inhibits MET phosphorylation and subsequent downstream signaling pathways in order to inhibit tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. Tepotinib has also been observed to down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (e.g. MMP7, COX-2, WNT1, MUC5B, and c-MYC) and upregulate the expression of EMT-suppressing genes (e.g. MUC5AC, MUC6, GSK3, and E-cadherin) in c-MET-amplified gastric cancer cells, suggesting that the tumor-suppressing activity of tepotinib is driven, at least in part, by the negative regulation of c-MET-induced EMT. It has also been shown to inhibit melatonin 1B and nischarin at clinically relevant concentrations, though the relevance of this activity in regards to tepotinib's mechanism of action is unclear.


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US Patents

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33rd NZW-Hamburg
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TEPOTINIB HYDROCHLORIDE

US Patent Number : 9284300

Drug Substance Claim :

Drug Product Claim : Y

Application Number : 214096

Patent Use Code :

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-04-29

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 8658643

Drug Substance Claim :

Drug Product Claim :

Application Number : 214096

Patent Use Code : U-3077

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-07-04

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 8927540

Drug Substance Claim :

Drug Product Claim :

Application Number : 214096

Patent Use Code : U-3078

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-07-21

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 9403799

Drug Substance Claim :

Drug Product Claim :

Application Number : 214096

Patent Use Code : U-3077

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-07-04

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 8580781

Drug Substance Claim : Y

Drug Product Claim : Y

Application Number : 214096

Patent Use Code :

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2030-03-19

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 8329692

Drug Substance Claim : Y

Drug Product Claim : Y

Application Number : 214096

Patent Use Code :

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2029-10-30

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 8921357

Drug Substance Claim : Y

Drug Product Claim : Y

Application Number : 214096

Patent Use Code :

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-05-30

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TEPOTINIB HYDROCHLORIDE

US Patent Number : 9062029

Drug Substance Claim :

Drug Product Claim : Y

Application Number : 214096

Patent Use Code :

Delist Requested :

Patent Use Description :

Patent Expiration Date : 2028-07-04

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ABOUT THIS PAGE

Tepotinib Manufacturers

A Tepotinib manufacturer is defined as any person or entity involved in the manufacture, preparation, processing, compounding or propagation of Tepotinib, including repackagers and relabelers. The FDA regulates Tepotinib manufacturers to ensure that their products comply with relevant laws and regulations and are safe and effective to use. Tepotinib API Manufacturers are required to adhere to Good Manufacturing Practices (GMP) to ensure that their products are consistently manufactured to meet established quality criteria.

click here to find a list of Tepotinib manufacturers with USDMF, JDMF, KDMF, CEP, GMP, COA and API Price related information on PhamaCompass.

Tepotinib Suppliers

A Tepotinib supplier is an individual or a company that provides Tepotinib active pharmaceutical ingredient (API) or Tepotinib finished formulations upon request. The Tepotinib suppliers may include Tepotinib API manufacturers, exporters, distributors and traders.

click here to find a list of Tepotinib suppliers with USDMF, JDMF, KDMF, CEP, GMP, COA and API Price related information on PharmaCompass.

Tepotinib GMP

Tepotinib Active pharmaceutical ingredient (API) is produced in GMP-certified manufacturing facility.

GMP stands for Good Manufacturing Practices, which is a system used in the pharmaceutical industry to make sure that goods are regularly produced and monitored in accordance with quality standards. The FDA’s current Good Manufacturing Practices requirements are referred to as cGMP or current GMP which indicates that the company follows the most recent GMP specifications. The World Health Organization (WHO) has its own set of GMP guidelines, called the WHO GMP. Different countries can also set their own guidelines for GMP like China (Chinese GMP) or the EU (EU GMP).

PharmaCompass offers a list of Tepotinib GMP manufacturers, exporters & distributors, which can be sorted by USDMF, JDMF, KDMF, CEP (COS), WC, API price, and more, enabling you to easily find the right Tepotinib GMP manufacturer or Tepotinib GMP API supplier for your needs.

Tepotinib CoA

A Tepotinib CoA (Certificate of Analysis) is a formal document that attests to Tepotinib's compliance with Tepotinib specifications and serves as a tool for batch-level quality control.

Tepotinib CoA mostly includes findings from lab analyses of a specific batch. For each Tepotinib CoA document that a company creates, the USFDA specifies specific requirements, such as supplier information, material identification, transportation data, evidence of conformity and signature data.

Tepotinib may be tested according to a variety of international standards, such as European Pharmacopoeia (Tepotinib EP), Tepotinib JP (Japanese Pharmacopeia) and the US Pharmacopoeia (Tepotinib USP).

Inform the supplier about your product requirements, specifying if you need a product with particular monograph like EP (Ph. Eur.), USP, JP, BP, or any other quality. In addition, clarify whether you need hydrochloride (HCl), anhydricum, base, micronisatum or a specific level of purity. To find reputable suppliers, utilize the filters and select those certified by GMP, FDA, or any other certification as per your requirement.
For your convenience, we have listed synonyms and CAS numbers to help you find the best supplier. The use of synonyms and CAS numbers can be helpful in identifying potential suppliers, but it is crucial to note that they might not always indicate the exact same product. It is important to confirm the product details with the supplier before making a purchase to ensure that it meets your requirements.
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