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Also known as: 936727-05-8, Vx-809, Vx 809, Vx809, Vrt-826809, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Molecular Formula

C₂₄H₁₈F₂N₂O₅

Molecular Weight

452.4 g/mol

InChI Key

UFSKUSARDNFIRC-UHFFFAOYSA-N

FDA UNII

EGP8L81APK

Lumacaftor is a drug used in combination with [DB08820] as the fixed dose combination product Orkambi for the management of Cystic Fibrosis (CF) in patients aged 6 years and older. Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a transmembrane ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Mutations in the CFTR gene result in altered production, misfolding, or function of the CFTR protein and consequently abnormal fluid and ion transport across cell membranes. As a result, CF patients produce thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to infections, lung damage, pancreatic insufficiency, and malnutrition. Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR proteins, preventing misfolding and resulting in increased processing and trafficking of mature protein to the cell surface. Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, increased weight gain, and improvements in CF symptoms. This data has been heavily scrutinized, however, with clinical trials showing only modest improvements despite a hefty yearly cost of $259,000 for Orkambi. Improvements in lung function (ppFEV1) were found to be statistically significant, but minimal, with only a 2.6-3.0% change from baseline with more than 70% of patients failing to achieve an absolute improvement of at least 5%. A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR, or delta-F508 (F508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes. When used in combination with [DB08820] as the fixed dose combination product Orkambi, lumacaftor is specific for the management of CF in patients with delta-F508 mutations as it acts as a protein-folding chaperone, aiding the conformational stability of the mutated CFTR protein. Consequently, lumacaftor increases successful production of CFTR ion channels and the total number of receptors available for use at the cell membrane for fluid and ion transport. The next most common mutation, G551D, affecting 4-5% of CF patients worldwide, is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered. Treatment of patients with G551D and other rarer missense mutations is usually managed with [DB08820] (Kalydeco), as it aids with altered gating mechanisms by potentiating channel opening probability of CFTR protein. Prior to the development of lumacaftor and [DB08820] (Kalydeco), management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process. Approved for use by the Food and Drug Administration in July 2015 and by Health Canada in January 2016, Orkambi was the first combination product approved for the management of Cystic Fibrosis with delta-F508 mutations. Ivacaftor is manufactured and distributed by Vertex Pharmaceuticals.

The mechanism of action of lumacaftor is as a Cytochrome P450 3A Inducer, and Cytochrome P450 2B6 Inducer, and Cytochrome P450 2C8 Inducer, and Cytochrome P450 2C9 Inducer, and Cytochrome P450 2C19 Inducer, and Cytochrome P450 2C8 Inhibitor, and Cytochrome P450 2C9 Inhibitor, and P-Glycoprotein Inducer, and P-Glycoprotein Inhibitor.

1 2D Structure

Lumacaftor

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid

2.1.2 InChI

InChI=1S/C24H18F2N2O5/c1-13-5-8-19(27-20(13)14-3-2-4-15(11-14)21(29)30)28-22(31)23(9-10-23)16-6-7-17-18(12-16)33-24(25,26)32-17/h2-8,11-12H,9-10H2,1H3,(H,29,30)(H,27,28,31)

2.1.3 InChI Key

UFSKUSARDNFIRC-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=C(N=C(C=C1)NC(=O)C2(CC2)C3=CC4=C(C=C3)OC(O4)(F)F)C5=CC(=CC=C5)C(=O)O

2.2 Other Identifiers

2.2.1 UNII

EGP8L81APK

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Vx 809

2. Vx-809

3. Vx809

2.3.2 Depositor-Supplied Synonyms

1. 936727-05-8

2. Vx-809

3. Vx 809

4. Vx809

5. Vrt-826809

6. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid

7. Vrt 826809

8. Vx-809 (lumacaftor)

9. Egp8l81apk

10. 3-(6-{[1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-benzoicacid

11. 3-(6-{[1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-benzoic Acid

12. 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic Acid

13. Lumacaftor (usan)

14. 3-(6-{[1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic Acid

15. Lumacaftor [usan]

16. 3-(6-(1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic Acid

17. 3-(6-[[1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino]-3-methyl-pyridin-2-yl)-benzoic Acid

18. 3-(6-{[1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-be

19. 3-(6-{[1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)benzoic Acid

20. Benzoic Acid, 3-(6-(((1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl)carbonyl)amino)-3-methyl-2-pyridinyl)-

21. Lumacaftor [inn]

22. Lumacaftor [usan:inn]

23. Unii-egp8l81apk

24. Vx8

25. Lumacaftor [mi]

26. Lumacaftor (vx-809)

27. Lumacaftor [who-dd]

28. Lumacaftor(vx-809vx809)

29. Mls006011120

30. Schembl377028

31. Gtpl7481

32. Chembl2103870

33. Lumacaftor [orange Book]

34. Chebi:90951

35. Dtxsid30239523

36. Ex-a178

37. Hms3655e05

38. Orkambi Component Lumacaftor

39. Amy14931

40. Bcp02305

41. Bdbm50289703

42. Mfcd16659051

43. S1565

44. Zinc64033452

45. Akos015920205

46. Lumacaftor Component Of Orkambi

47. Ccg-269253

48. Cs-0479

49. Db09280

50. Pb19466

51. Ncgc00346550-01

52. Ncgc00346550-02

53. Ncgc00346550-05

54. Ac-23172

55. As-31756

56. Hy-13262

57. Smr004702901

58. Ft-0757817

59. Sw219911-1

60. A25628

61. D10134

62. J-690399

63. Q6703005

64. 3-(6-(1-(2,2-difluorobenzo(d) (1,3)dioxyl-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid

65. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) Cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid

66. 3-(6-{[1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic Acid; Vx-809

67. 3-(6-{[1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropanecarbonyl]amino}-3-methyl-pyridin-2-yl)benzoic Acid

2.4 Create Date

2007-08-20

3 Chemical and Physical Properties

Molecular Formula	C₂₄H₁₈F₂N₂O₅
Molecular Weight	452.4 g/mol
XLogP3	4.4
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	5
Exact Mass	452.11837800 g/mol
Monoisotopic Mass	452.11837800 g/mol
Topological Polar Surface Area	97.8 Å²
Heavy Atom Count	33
Formal Charge	0
Complexity	776
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

When given in combination with [DB08820] as the fixed dose combination product Orkambi, lumacaftor is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.

FDA Label

Treatment of cystic fibrosis

5 Pharmacology and Biochemistry

5.1 Pharmacology

Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ [DB08820]) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life. Orkambi was not found to increase the QTc interval to any clinically relevant extent.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

LUMACAFTOR

5.2.2 FDA UNII

EGP8L81APK

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors

5.3 ATC Code

R07AX30

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

5.4 Absorption, Distribution and Excretion

Absorption

Following administration of Orkambi (lumacaftor/[DB08820]) with fat containing foods, peak plasma concentrations were reached at 4 hours (Tmax). It's recommended that Orkambi should be taken with fat-containing foods as they increase absorption of lumacaftor by approximately 2-fold, and[DB08820 by 3-fold.

Route of Elimination

Lumacaftor is primarily excreted unchanged in the feces (51%). A minimal amount of the parent compound and its metabolites are excreted in the urine.

Volume of Distribution

Following oral administration of 200 mg of lumacaftor every 24 hours to cystic fibrosis patients in a fed state for 28 days, the mean (+/-SD) for apparent volumes of distribution was 86.0 (69.8) L.

Clearance

The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr.

5.5 Metabolism/Metabolites

Lumacaftor is mostly excreted unchanged in the feces and is not extensively metabolized. When metabolism does occur, oxidation and glucuronidation are the main processes involved.

5.6 Biological Half-Life

The half-life of lumacaftor is approximately 26 hours.

5.7 Mechanism of Action

Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. More specifically, lumacaftor acts as a protein-folding chaperone, preventing misfolding of CFTR ion channels and consequent destruction during processing in the endoplasmic reticulum.

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