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Elexacaftor/Ivacaftor/Tezacaftor

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Also known as: 2216712-66-0, Vx-445, Elexacaftor [usan], Rrn67gmb0v, Elexacaftor (usan), (s)-n-((1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide

Molecular Formula

C₂₆H₃₄F₃N₇O₄S

Molecular Weight

597.7 g/mol

InChI Key

MVRHVFSOIWFBTE-INIZCTEOSA-N

FDA UNII

RRN67GMB0V

Elexacaftor (previously VX-445) is a small molecule, next-generation corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It received FDA approval in October 2019 in combination with [tezacaftor] and [ivacaftor] as the combination product TrikaftaTM. Elexacaftor is considered a next-generation CFTR corrector as it possesses both a different structure and mechanism as compared to first generation correctors like tezacaftor. While dual corrector/potentiator combination therapy has proven useful in the treatment of a subset of CF patients, their use is typically limited to patients who are homozygous for the F508del-CFTR gene. Elexacaftor, along with [VX-659], was designed to fill the need for an efficacious CF therapy for patients who are heterozygous for F508del-CFTR and a gene that does not produce protein or produces proteins unresponsive to ivacaftor or tezacaftor. The triple combination product TrikaftaTM, manufactured by Vertex Pharmaceuticals, is the first product approved for the treatment of CF in individuals who are either homo- or heterozygous for the F508del-CFTR gene - this represents approximately 70-90% of all CF patients.

1 2D Structure

Elexacaftor

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

2.1.2 InChI

InChI=1S/C26H34F3N7O4S/c1-16-12-25(5,6)35(13-16)22-18(23(37)33-41(38,39)19-14-34(7)31-17(19)2)8-9-20(30-22)36-11-10-21(32-36)40-15-24(3,4)26(27,28)29/h8-11,14,16H,12-13,15H2,1-7H3,(H,33,37)/t16-/m0/s1

2.1.3 InChI Key

MVRHVFSOIWFBTE-INIZCTEOSA-N

2.1.4 Canonical SMILES

CC1CC(N(C1)C2=C(C=CC(=N2)N3C=CC(=N3)OCC(C)(C)C(F)(F)F)C(=O)NS(=O)(=O)C4=CN(N=C4C)C)(C)C

2.1.5 Isomeric SMILES

C[C@H]1CC(N(C1)C2=C(C=CC(=N2)N3C=CC(=N3)OCC(C)(C)C(F)(F)F)C(=O)NS(=O)(=O)C4=CN(N=C4C)C)(C)C

2.2 Other Identifiers

2.2.1 UNII

RRN67GMB0V

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 3-pyridinecarboxamide, N-((1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)-2-((4s)-2,2,4-trimethyl-1-pyrrolidinyl)-

2. Vx-445

3. Vx445

2.3.2 Depositor-Supplied Synonyms

1. 2216712-66-0

2. Vx-445

3. Elexacaftor [usan]

4. Rrn67gmb0v

5. Elexacaftor (usan)

6. (s)-n-((1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide

7. 3-pyridinecarboxamide, N-((1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)-2-((4s)-2,2,4-trimethyl-1-pyrrolidinyl)-

8. N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4s)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

9. (6p)-n-(1,3-dimethyl-1h-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl]-2-[(4s)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

10. Wjx

11. Elexacaftor [mi]

12. Unii-rrn67gmb0v

13. Elexacaftor [inn]

14. Elexacaftor (vx-445)

15. Elexacaftor [who-dd]

16. Elexacaftor/ivacaftor/tezacaftor

17. Chembl4298128

18. Schembl20239811

19. Gtpl10552

20. Elexacaftor [orange Book]

21. Dtxsid901027907

22. Ex-a3637

23. S8851

24. Trikafta Component Elexacaftor

25. Vx-445vx-445

26. Who 11180

27. At16051

28. Db15444

29. Elexacaftor Component Of Trikafta

30. Compound 1 [wo2018107100a1]

31. Ac-36746

32. Hy-111772

33. Cs-0090942

34. D11507

35. A930250

2.4 Create Date

2018-06-23

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₃₄F₃N₇O₄S
Molecular Weight	597.7 g/mol
XLogP3	4.9
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	8
Exact Mass	597.23450825 g/mol
Monoisotopic Mass	597.23450825 g/mol
Topological Polar Surface Area	133 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	1050
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

Elexacaftor, in combination with [ivacaftor] and [tezacaftor] as the combination product Trikafta^TM, is indicated for the treatment of cystic fibrosis (CF) in patients 12 years of age and older who have at least one _F508del_ mutation in the CTFR gene.

5 Pharmacology and Biochemistry

5.1 Pharmacology

As a CFTR corrector, elexacaftor works to increase the amount of mature CFTR proteins present on the surface of cells. When used in combination with CFTR potentiators, which enhance the function of cell-surface CFTR proteins, drugs like elexacaftor help to improve a variety of multi-organ cystic fibrosis symptoms, including lung function, nutritional status, and overall quality of life. Trikafta^TM, the triple combination product containing elexacaftor, may cause elevations in liver transaminases. Liver function testing should be conducted prior to beginning Trikafta, every 3 months for the first year of treatment, and annually thereafter.

5.2 MeSH Pharmacological Classification

Chloride Channel Agonists

A class of drugs that stimulate chloride ion influx through cell membrane channels. (See all compounds classified as Chloride Channel Agonists.)

5.3 Absorption, Distribution and Excretion

Absorption

The absolute oral bioavailability of elexacaftor is approximately 80%. The steady-state AUC_0-24h and C_max following once daily dosing with elexacaftor 200mg are 162 mcgh/mL and 8.7 mcg/mL, respectively, and the median T_max is 6 hours. The AUC of elexacaftor is increased 1.9-2.5-fold following a moderate-fat meal - for this reason, it is recommended to give Trikafta^TM with fat-containing food.

Route of Elimination

Approximately 87.3% of an administered radio-labeled dose of elexacaftor was found in the feces, mostly as metabolites, while only 0.23% of that same dose was found excreted in the urine.

Volume of Distribution

The apparent volume of distribution of elexacaftor is 53.7 L.

Clearance

The mean apparent clearance of elexacaftor is 1.18 L/h.

5.4 Metabolism/Metabolites

The metabolism of elexacaftor is extensive and primarily catalyzed via CYP3A4/5. Its main active metabolite, M23-ELX, carries a similar potency as the parent drug. The precise metabolic pathway of elexacaftor has not yet been elucidated in published research.

5.5 Biological Half-Life

The mean terminal half-life of elexacaftor is approximately 24.7 hours.

5.6 Mechanism of Action

Cystic fibrosis (CF) is the result of a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR proteins produced by this gene are transmembrane ion channels that move sodium and chloride across cell membranes - water follows the flow of chloride ions to the cell surface, which consequently helps to hydrate the surface of the cell and thin the secretions (i.e. mucous) around the cell. Mutations in the CFTR gene produce CFTR proteins of insufficient quantity and/or function, leading to defective ion transport and a build-up of thick mucous throughout the body that causes multi-organ disease involving the pulmonary, gastrointestinal, and pancreatic systems (amongst others). The most common CFTR mutation, the _F508del_ mutation, is estimated to account for 70 to 90% of all CFTR mutations and results in severe processing and trafficking defects of the CFTR protein. Elexacaftor is a CFTR corrector that modulates CFTR proteins to facilitate trafficking to the cell surface for incorporation into the cell membrane. The end result is an increase in the number of mature CFTR proteins present at the cell surface and, therefore, improved ion transport and CF symptomatology. Elexacaftor is used in combination with tezacaftor, another CFTR corrector with a different mechanism of action, and ivacaftor, a CFTR potentiator that improves the function of CFTR proteins on the cell surface - this multi-faceted, triple-drug approach confers a synergistic effect beyond that seen in typical corrector/potentiator dual therapy regimens.

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