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Chemistry

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Also known as: 1454846-35-5, Pf-06463922, Loratinib, Lorbrena, Pf06463922, Pf 06463922

Molecular Formula

C₂₁H₁₉FN₆O₂

Molecular Weight

406.4 g/mol

InChI Key

IIXWYSCJSQVBQM-LLVKDONJSA-N

FDA UNII

OSP71S83EU

Lorlatinib is an orally available, ATP-competitive inhibitor of the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (Ros1), with potential antineoplastic activity. Upon administration, lorlatinib binds to and inhibits both ALK and ROS1 kinases. The kinase inhibition leads to disruption of ALK- and ROS1-mediated signaling and eventually inhibits tumor cell growth in ALK- and ROS1-overexpressing tumor cells. In addition, PF-06463922 is able to cross the blood brain barrier. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. ROS1, overexpressed in certain cancer cells, plays a key role in cell growth and survival of cancer cells.

Lorlatinib is a Kinase Inhibitor. The mechanism of action of lorlatinib is as a Kinase Inhibitor, and Cytochrome P450 3A Inducer, and P-Glycoprotein Inducer, and Cytochrome P450 2B6 Inducer, and Organic Cation Transporter 1 Inhibitor, and Organic Anion Transporter 3 Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Breast Cancer Resistance Protein Inhibitor.

1 2D Structure

Lorlatinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(16R)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10(15),11,13,18,20-octaene-3-carbonitrile

2.1.2 InChI

InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1

2.1.3 InChI Key

IIXWYSCJSQVBQM-LLVKDONJSA-N

2.1.4 Canonical SMILES

CC1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C

2.1.5 Isomeric SMILES

C[C@@H]1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C

2.2 Other Identifiers

2.2.1 UNII

OSP71S83EU

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (10r)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile

2. 7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile

3. Loratinib

4. Lorbrena

5. Pf-06463922

6. Pf06463922

2.3.2 Depositor-Supplied Synonyms

1. 1454846-35-5

2. Pf-06463922

3. Loratinib

4. Lorbrena

5. Pf06463922

6. Pf 06463922

7. Osp71s83eu

8. Chembl3286830

9. C21h19fn6o2

10. (10r)-7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-2h-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile

11. (16r)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10(15),11,13,18,20-octaene-3-carbonitrile

12. 2h-4,8-methenopyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10r)-

13. Lorviqua

14. Mfcd28144520

15. (10r)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile

16. Unii-osp71s83eu

17. Lorlatinibum

18. Lorlatinib,pf-06463922

19. Pf-6463922

20. 4cli

21. 4clj

22. Lorbrena (tn)

23. 2h-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10r)-

24. Lorlatinib [mi]

25. Lorlatinib [inn]

26. Lorlatinib [jan]

27. Lorlatinib [usan:inn]

28. Lorlatinib [usan]

29. Pfe-pkis 10

30. Lorlatinib [who-dd]

31. 7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile

32. Lorlatinib (jan/usan/inn)

33. Pf06463922(lorlatinib)

34. Gtpl7476

35. Lorlatinib [orange Book]

36. Pf-06463922 Lorlatinib

37. Schembl15261807

38. Amy3295

39. Ex-a828

40. Chebi:143117

41. Dtxsid201027944

42. Bcp10287

43. Bdbm50018830

44. Nsc780108

45. Nsc800990

46. S7536

47. Zinc98208524

48. Akos027250753

49. Ccg-268718

50. Cs-3983

51. Db12130

52. Nsc-780108

53. Nsc-800990

54. Ncgc00386417-02

55. Ncgc00386417-13

56. Ac-30881

57. Hy-12215

58. A14207

59. D11012

60. A857523

61. J-690185

62. Q27285820

63. (10r)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-4,8- Methenopyrazolo(4,3-h)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile

64. (10r)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile

65. (r)-26-amino-55-fluoro-11,4,7-trimethyl-6-oxo-11h-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphane-15-carbonitrile

2.4 Create Date

2013-10-17

3 Chemical and Physical Properties

Molecular Formula	C₂₁H₁₉FN₆O₂
Molecular Weight	406.4 g/mol
XLogP3	1.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	0
Exact Mass	406.15535203 g/mol
Monoisotopic Mass	406.15535203 g/mol
Topological Polar Surface Area	110 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	700
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
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

Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease.

FDA Label

Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)positive advanced nonsmall cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.

Lorviqua as monotherapy is indicated for the treatment of adult patients with ALKpositive advanced NSCLC whose disease has progressed after:

- alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or

- crizotinib and at least one other ALK TKI.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Based on data from Study B7461001, exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure. In 295 patients who received lorlatinib at the recommended dosage of 100 mg once daily and had an ECG measurement in the same Study B7461001, the maximum mean change from baseline for their PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation 200 ms after starting use with lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner and atrioventricular block occurred in 1% of patients. Finally, in 275 patients who received lorlatinib at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

LORLATINIB

5.2.2 FDA UNII

OSP71S83EU

5.2.3 Pharmacological Classes

Kinase Inhibitor [EPC]; Kinase Inhibitors [MoA]; Cytochrome P450 3A4 Inducers [MoA]

5.3 ATC Code

L01ED05

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01ED - Anaplastic lymphoma kinase (alk) inhibitors

L01ED05 - Lorlatinib

5.4 Absorption, Distribution and Excretion

Absorption

The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state. The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration. Administration of lorlatinib with a high fat, high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) had no clinically meaningful effect on lorlatinib pharmacokinetics.

Route of Elimination

Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).

Volume of Distribution

The mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose.

Clearance

The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction.

5.5 Metabolism/Metabolites

In vitro, lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3. In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity in a human [14C] mass balance study. The oxidative cleavage metabolite, M8, is pharmacologically inactive.

5.6 Biological Half-Life

The mean plasma half-life (t) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib.

5.7 Mechanism of Action

Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancer cases worldwide and remains a particularly difficult to treat condition. The gene rearrangement of anaplastic lymphoma kinase (ALK) is a genetic alteration that drives the development of NSCLC in a number of patients. Ordinarily, ALK is a natural endogenous tyrosine kinase receptor that plays an important role in the development of the brain and elicits activity on various specific neurons in the nervous system. Subsequnetly, lorlatinib is a kinase inhibitor with in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. The overall antitumor activity of lorlatinib in in-vivo models appears to be dose-dependent and correlated with the inhibition of ALK phosphorylation. Although many ALK-positive metastatic NSCLC patients respond to initial tyrosine kinase therapies, such patients also often experience tumor progression. Various clinical trials performed with lorlatinib, however, have demonstrated its utility to effect tumor regression in ALK-positive metastatic NSCLC patients who experience tumor progression despite current use or having already used various first and second-generation tyrosine kinase inhibitors like crizotinib, alectinib, or ceritinib.

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