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CAS 1421373-65-0
PharmaCompass
  • Chemistry
CAS 1421373-65-0
Also known as: Azd-9291, 1421373-65-0, Mereletinib, Azd9291, Tagrisso, Azd 9291
Molecular Formula
C28H33N7O2
Molecular Weight
499.619  g/mol
InChI Key
DUYJMQONPNNFPI-UHFFFAOYSA-N
FDA UNII
3C06JJ0Z2O

Osimertinib is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals. Its use is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in cases where tumour EGFR expression is positive for the T790M mutation as detected by FDA-approved testing and which has progressed following therapy with a first-generation EGFR tyrosine kinase inhibitor. Approximately 10% of patients with NSCLC have a rapid and clinically effective response to EGFR-TKIs due to the presence of specific activating EGFR mutations within the tumour cells. More specifically, deletions around the LREA motif in exon 19 and exon 21 L858R point mutations are correlated with response to therapy. Development of third-generation EGFR-TKIs, such as osimertinib, has been in response to altered tumour resistance patterns following treatment and toxic side effects that impact patient quality of life. Treatment with first-generation EGFR-TKIs (gefitinib and erlotinib) has been associated with the development of resistance through activating mutations in the EGFR gene. Second-generation EGFR-TKIs (afatinib and dacomitinib) were then developed to be more potent inhibitors, although their use is associated with increased toxicity through nonspecific targeting of wild-type EGFR. In contrast, third-generation inhibitors are specific for the gate-keeper T790M mutations which increases ATP binding activity to EGFR and result in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.
Osimertinib is a Kinase Inhibitor. The mechanism of action of osimertinib is as a Kinase Inhibitor, and Cytochrome P450 3A Inhibitor, and Cytochrome P450 3A4 Inducer, and Cytochrome P450 1A2 Inducer, and Breast Cancer Resistance Protein Inhibitor.
1 2D Structure

CAS 1421373-65-0

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
2.1.2 InChI
InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
2.1.3 InChI Key
DUYJMQONPNNFPI-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC
2.2 Other Identifiers
2.2.1 UNII
3C06JJ0Z2O
2.3 Synonyms
2.3.1 Depositor-Supplied Synonyms

1. Azd-9291

2. 1421373-65-0

3. Mereletinib

4. Azd9291

5. Tagrisso

6. Azd 9291

7. Unii-3c06jj0z2o

8. 3c06jj0z2o

9. N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

10. Ak170511

11. N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide

12. N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1h-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide

13. Mereletinib [inn]

14. Osimertinib [usan]

15. Osimertinib Mesilate

16. Tube720

17. D0rt2c

18. Mereletinib (obsolete Inn)

19. Gtpl7719

20. Chembl3353410

21. Schembl14660911

22. Chebi:90943

23. Aob6268

24. Ex-a314

25. Duyjmqonpnnfpi-uhfffaoysa-n

26. Molport-035-395-886

27. C28h33n7o2

28. Hms3653e10

29. Ks-000007zw

30. Abp001123

31. Bdbm50029668

32. Mfcd27988062

33. S7297

34. Zinc98023177

35. Akos025290756

36. Cs-2018

37. Db09330

38. 2-propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1h-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-

39. 4ca-0243

40. As-16943

41. Hy-15772

42. Qc-11454

43. Sc-94470

44. Kb-330516

45. Ft-0696828

46. X3507

47. Mereletinib Pound Azd-9291 Osimertinib Pound(c)

48. 1610419-47-0

49. N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

2.4 Create Date
2013-06-10
3 Chemical and Physical Properties
Molecular Weight 499.619 g/mol
Molecular Formula C28H33N7O2
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count7
Rotatable Bond Count10
Exact Mass499.27 g/mol
Monoisotopic Mass499.27 g/mol
Topological Polar Surface Area87.6 A^2
Heavy Atom Count37
Formal Charge0
Complexity752
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 Information
1 of 1  
Drug NameTAGRISSO
Active IngredientOSIMERTINIB MESYLATE
CompanyASTRAZENECA PHARMS (Application Number: N208065. Patents: 8946235, 9732058)

4.2 Drug Indication

Osimertinib is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA- approved test, who have progressed on or after EGFR-TKI therapy.


FDA Label


TAGRISSO is indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC).


5 Pharmacology and Biochemistry
5.1 Pharmacology

A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg.


Osimertinib is a third-generation, orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, osimertinib covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. AZD9291 preferentially inhibits mutated forms of EGFR including T790M, a secondarily-acquired resistance mutation, and may have enhanced anti-tumor effects in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced when compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR.


5.2 FDA Pharmacological Classification
5.2.1 Active Moiety

OSIMERTINIB


5.2.2 FDA UNII

3C06JJ0Z2O


5.2.3 Pharmacological Classes

Established Pharmacologic Class [EPC]

Kinase Inhibitor


Mechanisms of Action [MoA]

Kinase Inhibitors


Mechanisms of Action [MoA]

Cytochrome P450 3A Inhibitors


Mechanisms of Action [MoA]

Cytochrome P450 3A4 Inducers


Mechanisms of Action [MoA]

Cytochrome P450 1A2 Inducers


Mechanisms of Action [MoA]

Breast Cancer Resistance Protein Inhibitors


5.3 ATC Code

Anatomical main group: L - Antineoplastic and immunomodulating agents
Therapeutic subgroup: L01 - Antineoplastic agents
Pharmacological subgroup: L01X - Other antineoplastic agents
Chemical subgroup: L01XE - Protein kinase inhibitors
Chemical substance: L01XE35 - osimertinib


L - Antineoplastic and immunomodulating agents
L01 - Antineoplastic agents
L01X - Other antineoplastic agents
L01XE - Protein kinase inhibitors
L01XE35 - Osimertinib


5.4 Absorption, Distribution and Excretion

Absorption

The median time to Cmax was found to be 6 hours.


Route of Elimination

Osimertinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.


Volume of Distribution

The mean volume of distribution at steady state is 986 L.


Clearance

Oral clearance is 14.2 L/hr.


5.5 Metabolism/Metabolites

Metabolism

Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, that circulate at approximately 10% of the concentration of the parent compound. Biochemical assays have shown that AZ7550 has similar potency and efficacy to osimertinib, while AZ5104 is more potent against mutant and wild-type EGFR. The main metabolic pathways are oxidation (predominantly by CYP3A) and dealkylation.


5.6 Biological Half-Life

The population estimated mean half-life is 48 hours.


5.7 Mechanism of Action

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.


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