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Also known as: Vx-661, 1152311-62-0, Tezacaftor (vx-661), Tezacaftor [usan], (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide, Vx661

Molecular Formula

C₂₆H₂₇F₃N₂O₆

Molecular Weight

520.5 g/mol

InChI Key

MJUVRTYWUMPBTR-MRXNPFEDSA-N

FDA UNII

8RW88Y506K

Tezacaftor is a drug of the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator class. It was developed by Vertex Pharmaceuticals and FDA approved in combination with [ivacaftor] to manage cystic fibrosis. This drug was approved by the FDA on February 12, 2018. 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, an ion channel involved in the transport of chloride and sodium ions across cell membranes. CFTR is active in epithelial cells of organs such as of the lungs, pancreas, liver, digestive system, and reproductive tract. Alterations in the CFTR gene result in altered production, misfolding, or function of the 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 complications such as infections, lung damage, pancreatic insufficiency, and malnutrition.

1 2D Structure

Tezacaftor

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide

2.1.2 InChI

InChI=1S/C26H27F3N2O6/c1-24(2,13-33)22-8-14-7-18(17(27)10-19(14)31(22)11-16(34)12-32)30-23(35)25(5-6-25)15-3-4-20-21(9-15)37-26(28,29)36-20/h3-4,7-10,16,32-34H,5-6,11-13H2,1-2H3,(H,30,35)/t16-/m1/s1

2.1.3 InChI Key

MJUVRTYWUMPBTR-MRXNPFEDSA-N

2.1.4 Canonical SMILES

CC(C)(CO)C1=CC2=CC(=C(C=C2N1CC(CO)O)F)NC(=O)C3(CC3)C4=CC5=C(C=C4)OC(O5)(F)F

2.1.5 Isomeric SMILES

CC(C)(CO)C1=CC2=CC(=C(C=C2N1C[C@H](CO)O)F)NC(=O)C3(CC3)C4=CC5=C(C=C4)OC(O5)(F)F

2.2 Other Identifiers

2.2.1 UNII

8RW88Y506K

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Vx-661

2.3.2 Depositor-Supplied Synonyms

1. Vx-661

2. 1152311-62-0

3. Tezacaftor (vx-661)

4. Tezacaftor [usan]

5. (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide

6. Vx661

7. Vx 661

8. 8rw88y506k

9. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl}cyclopropane-1-carboxamide

10. Unii-8rw88y506k

11. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide

12. Cv6

13. Cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-(1-((2r)-2,3-dihydroxypropyl)-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1h-indol-5-yl)-

14. Tezacaftor [mi]

15. Tezacaftor [inn]

16. Tezacaftor (usan/inn)

17. Tezacaftor [who-dd]

18. Schembl322362

19. Vx 661;vx661;tezacaftor

20. Chembl3544914

21. Schembl10034144

22. Tezacaftor [orange Book]

23. Gtpl10199

24. Dtxsid40673070

25. Bdbm281054

26. Symkevi Component Tezacaftor

27. Bcp07173

28. Cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1h-indol-5-yl]-

29. Ex-a1759

30. Trikafta Component Tezacaftor

31. Mfcd23106064

32. S7059

33. Us10022352, Compound 315

34. Zinc68206930

35. Ccg-269854

36. Cs-1078

37. Db11712

38. Tezacaftor Component Of Trikafta

39. 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide

40. Ac-32773

41. As-35211

42. Hy-15448

43. Example 315 [us20090131492a1]

44. Sw219937-1

45. D11041

46. A857959

47. Q27270940

48. (r)-1 (2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide

49. (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropane-1-carboxamide

50. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-~{n}-[1-[(2~{r})-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide

51. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-(1-((2r)-2,3-dihydroxypropyl)-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1h-indol-5-yl)cyclopropanecarboxamide

52. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1h-indol-5-yl]-cyclopropanecarboxamide

53. Vx661; Vx 661; Tezacaftor;(r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide

2.4 Create Date

2010-07-06

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₂₇F₃N₂O₆
Molecular Weight	520.5 g/mol
XLogP3	2.9
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	8
Exact Mass	520.18212107 g/mol
Monoisotopic Mass	520.18212107 g/mol
Topological Polar Surface Area	113 Å²
Heavy Atom Count	37
Formal Charge	0
Complexity	858
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

Tezacaftor is combined with ivacaftor in one product for the treatment of cystic fibrosis (CF) in patients aged 12 years or older with two copies of the _F508del_ gene mutation or at least one mutation in the CFTR gene that is responsive to this drug. Tezacaftor, when used in combination with ivacaftor and [elexacaftor] in the product Trikafta, is also indicated for the treatment of CF in patients 12 years of age and older that have at least one _F508del_ mutation in the CFTR gene.

FDA Label

5 Pharmacology and Biochemistry

5.1 Pharmacology

Clinical studies have shown a significant decrease in sweat chloride and an increase in the forced expiratory volume (FEV), a measure of lung function, following Tevacaftor/Ivacaftor therapy. Phase 3 clinical studies have shown that a significant increase in forced expiratory volume was attained at 4 and 8 weeks after initiating this drug. The above effects lead to improvement of the respiratory symptoms of cystic fibrosis. Tezacaftor does not induce clinically significant QT prolongation. When given with ivacaftor, tezacaftor can lead to liver transaminase elevations. Testing of transaminases (ALT and AST) levels should occur before starting this combination every 3 months during the first year of treatment, and every year afterwards. Patients with a history of transaminase elevations should be monitored more frequently.

5.2 Absorption, Distribution and Excretion

Absorption

The Cmax, Tmax and AUC of tezacaftor, when administered with ivacaftor, are 5.95 mcg/ml, 2-6 h, and 84.5 mcg.h/ml respectively. Exposure of tezacaftor/ivacaftor increases 3-fold when it is administered with a high-fat meal.

Route of Elimination

After oral administration, the majority of tezacaftor dose (72%) is found excreted in the feces either unchanged or as its metabolite, M2. About 14% of the administered dose is found excreted in the urine as the metabolite, M2. It was noted that less than 1% of the administered dose is excreted unchanged in the urine and thus, renal excretion is not the major elimination pathway.

Volume of Distribution

The apparent volume of distribution of tezacaftor was 271 L in a study of patients in the fed state who received 100 mg of tezacaftor every 12 hours.

Clearance

The apparent clearance of tezacaftor has been measured at 1.31 L/h for patients in the fed state during a clinical trial.

5.3 Metabolism/Metabolites

Tezacaftor is metabolized extensively in humans by the action of CYP3A4 and CYP3A5. There are three main circulating metabolites; M1, M2, and M5. The M1 is an active metabolite with similar activity to the parent drug, tezacaftor. The M2 metabolite is significantly less active and M5 is considered an inactive metabolite. An additional circulating metabolite, M3, corresponding to the glucuronide form of tezacaftor.

5.4 Biological Half-Life

The apparent half-life of tezacaftor is approximately 57.2 hours.

5.5 Mechanism of Action

The transport of charged ions across cell membranes is normally achieved through the actions of the cystic fibrosis transmembrane regulator (CFTR) protein. This protein acts as a channel and allows for the passage of chloride and sodium. This process affects the movement of water in and out of the tissues and impacts the production of mucus that lubricates and protects certain organs and body tissues, including the lungs. In the _F508del_ mutation of the CFTR gene, one amino acid is deleted at the position 508, therefore, the CFTR channel function is compromised, resulting in thickened mucus secretions. CFTR correctors such as tezacaftor aim to repair F508del cellular misprocessing. This is done by modulating the position of the CFTR protein on the cell surface to the correct position, allowing for adequate ion channel formation and increased in water and salt movement through the cell membrane. The concomitant use of ivacaftor is intended to maintain an open channel, increasing the transport of chloride, reducing thick mucus production.

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