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Chemistry

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Also known as: 183321-74-6, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine, Tarceva, Erlotinib free base, 4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline, Osi-774

Molecular Formula

C₂₂H₂₃N₃O₄

Molecular Weight

393.4 g/mol

InChI Key

AAKJLRGGTJKAMG-UHFFFAOYSA-N

FDA UNII

J4T82NDH7E

A quinazoline derivative and ANTINEOPLASTIC AGENT that functions as a PROTEIN KINASE INHIBITOR for EGFR associated tyrosine kinase. It is used in the treatment of NON-SMALL CELL LUNG CANCER.

Erlotinib is a Kinase Inhibitor. The mechanism of action of erlotinib is as a Protein Kinase Inhibitor.

1 2D Structure

Erlotinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

2.1.2 InChI

InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)

2.1.3 InChI Key

AAKJLRGGTJKAMG-UHFFFAOYSA-N

2.1.4 Canonical SMILES

COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC

2.2 Other Identifiers

2.2.1 UNII

J4T82NDH7E

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 11c Erlotinib

2. 11c-erlotinib

3. 358,774, Cp

4. 358774, Cp

5. Cp 358,774

6. Cp 358774

7. Cp-358,774

8. Cp-358774

9. Cp358,774

10. Cp358774

11. Erlotinib Hcl

12. Erlotinib Hydrochloride

13. Hcl, Erlotinib

14. Hydrochloride, Erlotinib

15. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

16. Osi 774

17. Osi-774

18. Osi774

19. Tarceva

2.3.2 Depositor-Supplied Synonyms

1. 183321-74-6

2. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

3. Tarceva

4. Erlotinib Free Base

5. 4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline

6. Osi-774

7. 4-quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-

8. Erlotinib, Free Base

9. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

10. 183321-74-6 (free Base)

11. Nsc 718781

12. Chembl553

13. J4t82ndh7e

14. [6,7-bis(2-methoxy-ethoxy)quinazoline-4-yl]-(3-ethynylphenyl)amine

15. Cp358774

16. Cp-358,774

17. Chebi:114785

18. Mfcd02089651

19. Rg-1415

20. Ncgc00164574-01

21. [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine

22. Cp-35877401

23. R-1415

24. Dsstox_cid_26454

25. Dsstox_rid_81628

26. Dsstox_gsid_46454

27. Erlotinib(tarceva)

28. Osi-744

29. Cas-183321-74-6

30. Nsc718781

31. Erlotinib [inn:ban]

32. Sr-05000001460

33. Unii-j4t82ndh7e

34. Erlotinibum

35. Erotinib

36. Hsdb 8082

37. Osi 744

38. Nchembio866-comp3

39. Kinome_3317

40. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine Monohydrochloride

41. Erlotinib [mi]

42. Erlotinib [vandf]

43. R 1415

44. Erlotinib [who-dd]

45. Schembl8413

46. Erlotinib [ema Epar]

47. Bdbm5446

48. Cid_176870

49. Gtpl4920

50. Dtxsid8046454

51. Hms2089f05

52. Hms3244m19

53. Hms3244m20

54. Hms3244n19

55. Hms3295a19

56. Hms3713c22

57. Hms3745m05

58. Zinc1546066

59. Tox21_112202

60. Ac-399

61. Nsc800097

62. S7786

63. Stk623143

64. Akos000282911

65. Tox21_112202_1

66. Ccg-220420

67. Cs-0620

68. Db00530

69. Nsc-800097

70. Ro-508231

71. Sb16916

72. Ncgc00164574-03

73. Ncgc00164574-05

74. Ncgc00164574-06

75. Ncgc00164574-14

76. Ncgc00164574-25

77. As-35132

78. Bcb03_000783

79. Be164419

80. Hy-50896

81. Sy028059

82. Am20090621

83. Ft-0651539

84. R1415

85. K00241

86. Ab01273955-01

87. Ab01273955-02

88. Ab01273955-03

89. 321e746

90. Q418369

91. Sr-05000001460-1

92. Sr-05000001460-2

93. Sr-05000001460-3

94. Sr-05000001460-6

95. Brd-k70401845-003-04-7

96. 1429636-49-6

2.4 Create Date

2005-03-26

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₂₃N₃O₄
Molecular Weight	393.4 g/mol
XLogP3	3.3
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	11
Exact Mass	393.16885622 g/mol
Monoisotopic Mass	393.16885622 g/mol
Topological Polar Surface Area	74.7 Å²
Heavy Atom Count	29
Formal Charge	0
Complexity	525
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 2
Drug Name	Tarceva
PubMed Health	Erlotinib (By mouth)
Drug Classes	Antineoplastic Agent, Immunological Agent
Drug Label	TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:Erloti...
Active Ingredient	Erlotinib hydrochloride
Dosage Form	Tablet
Route	Oral
Strength	eq 100mg base; eq 150mg base; eq 25mg base
Market Status	Prescription
Company	Osi Pharms

2 of 2
Drug Name	Tarceva
PubMed Health	Erlotinib (By mouth)
Drug Classes	Antineoplastic Agent, Immunological Agent
Drug Label	TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:Erloti...
Active Ingredient	Erlotinib hydrochloride
Dosage Form	Tablet
Route	Oral
Strength	eq 100mg base; eq 150mg base; eq 25mg base
Market Status	Prescription
Company	Osi Pharms

4.2 Therapeutic Uses

Erlotinib hydrochloride monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20

Erlotinib hydrochloride monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. /Included in US product label/

Erlotinib hydrochloride in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. /Included in US product label/

4.3 Drug Warning

The manufacturer states that there are no known contraindications to the use of erlotinib.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040

Serious, sometimes fatal, interstitial lung disease-like events have occurred in patients receiving erlotinib. Interstitial lung disease-like events have been reported in approximately 0.7% of about 4900 patients receiving erlotinib in controlled and uncontrolled studies. In the principal efficacy study for non-small cell lung cancer, the reported incidence of interstitial lung disease-like events (0.8%) was similar among patients receiving erlotinib and those receiving placebo. In the principal efficacy study for pancreatic cancer, interstitial lung disease-like events occurred in 2.5% of patients receiving erlotinib and gemcitabine versus 0.4% of those receiving placebo and gemcitabine. Onset of manifestations occurred from 5 days to more than 9 months (median: 39 days) after initiating erlotinib therapy. Reported diagnoses in patients suspected of having interstitial lung disease-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration. Among patients receiving erlotinib for non-small cell lung cancer, most of these cases were associated with confounding or contributing factors, including concomitant or prior chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040

Interruption or discontinuance of erlotinib therapy may be required in patients experiencing pulmonary toxicity.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040

Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency, with or without hypokalemia, have been reported in patients receiving erlotinib. Factors contributing to these adverse renal effects included baseline hepatic impairment; severe dehydration caused by diarrhea, vomiting, and/or anorexia; and concurrent chemotherapy. If dehydration occurs, erlotinib therapy should be interrupted and rehydration measures should be initiated. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040

For more Drug Warnings (Complete) data for Erlotinib (27 total), please visit the HSDB record page.

4.4 Drug Indication

Erlotinib is indicated for: - The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. - In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy.

FDA Label

* Non-small cell lung cancer (NSCLC):

Tarceva is also indicated for switch maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with EGFR activating mutations and stable disease after first-line chemotherapy.

Tarceva is also indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

In patients with tumours without EGFR activating mutations, Tarceva is indicated when other treatment options are not considered suitable.

When prescribing Tarceva, factors associated with prolonged survival should be taken into account.

No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with Epidermal Growth Factor Receptor (EGFR)-IHC - negative tumours.

* Pancreatic cancer :

Tarceva in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer .

When prescribing Tarceva, factors associated with prolonged survival should be taken into account.

5 Pharmacology and Biochemistry

5.1 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Protein Kinase Inhibitors

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

ERLOTINIB

5.2.2 FDA UNII

J4T82NDH7E

5.2.3 Pharmacological Classes

Protein Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L01EB02

L01XE03

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

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

L01EB02 - Erlotinib

5.4 Absorption, Distribution and Excretion

Absorption

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib.

Route of Elimination

Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound).

Volume of Distribution

Apparent volume of distribution = 232 L

Clearance

Smokers have a 24% higher rate of erlotinib clearance.

Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein. Erlotinib has an apparent volume of distribution of 232 liters.

Time to reach steady state plasma concentration /is/ 7 - 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance.

Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).

For more Absorption, Distribution and Excretion (Complete) data for Erlotinib (10 total), please visit the HSDB record page.

5.5 Metabolism/Metabolites

Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1.

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of (14)C-erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject)... In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.

PMID:16381666 Ling J et al; Drug Metab Dispos 34 (3): 420-6 (2006)

Erlotinib has known human metabolites that include Erlotinib M14.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.6 Biological Half-Life

Median half-life of 36.2 hours.

A population pharmacokinetic analysis in 591 patients receiving the single-agent erlotinib hydrochloride 2nd/3rd line regimen showed a median half-life of 36.2 hours.

5.7 Mechanism of Action

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

Although the exact mechanism of antineoplastic activity of erlotinib has not been fully elucidated, erlotinib appears to inhibit the intracellular phosphorylation of tyrosine kinase associated with EGFR, which is expressed on the surface of normal and cancer cells. Specificity with regard to other tyrosine kinase receptors has not been fully characterized.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042

Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, /investigators/ aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-gamma of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.

PMID:21195724 Luo Q et al; Toxicol Appl Pharmacol 251 (2): 130-6 (2011)

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