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VX-770
- Iupac Name：N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
- CAS No.: 873054-44-5
- Molecular Weight：392.49
- Modify Date.: 2022-11-25 02:26
- Introduction: In January 2012, the US FDA approved ivacaftor for the treatment of cysticfibrosis (CF) in patients who have the G551D mutation of the CF transmembrane regulator (CFTR) and are at least 6 years old. Ivacaftor (also known as VX-770) is a CFTR potentiator that increases the open probability of CFTR, thus increasing chloridesecretion particularly in the 5% of CF patients with the G551D/F508 gating/processing mutation. Ivacaftor was discovered by medicinal chemistry optimization of a lead scaffold identified through high-throughput screening of a 228,000 compound collection. In cultured bronchial epithelial cells from a CF patient with F508del, ivacaftor increased chloride secretion(EC50=81 nM). Preparation of ivacaftor is accomplished via a multistepsynthesis oftwointermediates, 4-oxo-1,4-dihydroquinoline-3-carboxylic acidand 5-amino-di-tert-butylphenyl methyl carbonate, which are coupled usingpropane phosphonic acid anhydride (T3P) to afford the amide; deprotection ofthe phenol then provides ivacaftor.
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1. Names and Identifiers
- 1.1 Name
- VX-770
- 1.2 Synonyms
[14C]-Ivacaftor 3-QuinolinecarboxaMide, N-[2,4-bis(1,1-diMethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo- Ivacaftor Ivacaftor (VX-770) Kalydeco MFCD17171361 N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxaMide N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxaraide N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide Ivacaftor (VX-770) N-[5-Hydroxy-2,4-bis(2-methyl-2-propanyl)phenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide UNII-1Y740ILL1Z VX 770, Ivacaftor VX770
- 1.3 CAS No.
- 873054-44-5
- 1.4 CID
- 16220172
- 1.5 Molecular Formula
- C24H28N2O3 (isomer)
- 1.6 Inchi
- InChI=1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
- 1.7 InChkey
- PURKAOJPTOLRMP-UHFFFAOYSA-N
- 1.8 Canonical Smiles
- CC(C)(C)C1=CC(=C(C=C1NC(=O)C2=CNC3=CC=CC=C3C2=O)O)C(C)(C)C
- 1.9 Isomers Smiles
- CC(C)(C)C1=CC(=C(C=C1NC(=O)C2=CNC3=CC=CC=C3C2=O)O)C(C)(C)C
2. Properties
- 2.1 Density
- 1.187
- 2.1 Melting point
- 212-215
- 2.1 Boiling point
- 550.4 °C at 760 mmHg
- 2.1 Refractive index
- 1.606
- 2.1 Flash Point
- 286.7 °C
- 2.1 Precise Quality
- 392.209991
- 2.1 PSA
- 85.68000
- 2.1 logP
- 5.46500
- 2.1 Solubility
- low (<0.05 μg/mL)
- 2.2 Appearance
- Solid
- 2.3 pKa
- 11.08±0.23(Predicted)
- 2.4 Water Solubility
- H2O: <0.05 μg/mL
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with the amino group of 5-amino-2,4-di-tert-butylphenol. Used for the treatment of cystic fibrosis.
- 3.2 Usage
- Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively
4. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
no data available
2.2 GHS label elements, including precautionary statements
| Pictogram(s) | no data available |
| Signal word | no data available |
| Hazard statement(s) | no data available |
| Precautionary statement(s) | |
| Prevention | no data available |
| Response | no data available |
| Storage | no data available |
| Disposal | no data available |
2.3 Other hazards which do not result in classification
no data available
5. Synthesis Route
873054-44-5Total: 12 Synthesis Route
7. Other Information
- 7.0 Target
- Value
- 7.1 F508del-CFTR (Fisher rat thyroid cells)
- 25 nM(EC50)
- 7.2 G551D-CFTR (Fisher rat thyroid cells)
- 100 nM(EC50)
- 7.3 Description
- In January 2012, the US FDA approved ivacaftor for the treatment of cystic fibrosis (CF) in patients who have the G551D mutation of the CF transmembrane regulator (CFTR) and are at least 6 years old. Ivacaftor (also known as VX-770) is a CFTR potentiator that increases the open probability of CFTR, thus increasing chloride secretion particularly in the 5% of CF patients with the G551D/F508 gating/ processing mutation. Ivacaftor was discovered by medicinal chemistry optimization of a lead scaffold identified through high-throughput screening of a 228,000 compound collection. In cultured bronchial epithelial cells from a CF patient with F508del, ivacaftor increased chloride secretion (EC50=81 nM). Preparation of ivacaftor is accomplished via a multistep synthesis oftwointermediates, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-di-tert-butylphenyl methyl carbonate, which are coupled using propane phosphonic acid anhydride (T3P) to afford the amide; deprotection of the phenol then provides ivacaftor.
- 7.4 Originator
- Vertex Pharmaceuticals (United States)
- 7.5 Clinical Use
- Vertex’s ivacaftor was granted breakthrough therapy designation by the FDA in January 2012 for cystic fibrosis (CF) patients who bear the G551D mutation in the Cycstic Fibrosis Transmembrane Regulator (CFTR) gene. This CFTR mutation occurs in roughly 4% of the 30,000 people living with CF in the United States. While the compound has been identified as a potentiator in cell-based assays, its mechanism of action is as yet unknown.
- 7.6 Chemical Synthesis
- Several patents describe a synthesis of ivacaftor, only one demonstrates the synthesis on scale and includes yields, which is depicted in the scheme. Beginning with treatment of commercial di-tert-butylphenol derivative 91 with ethyl chloroformate, the synthesis of carbonate 92 was achieved in quantitative yield. Nitration of 92 provided the desired nitroarene regioisomer 93 in 57% yield which was isolated by recrystallization. Reduction of the newlyinstalled nitro group and subsequent amide bond formation via reaction with commercially available acid chloride 94 produced amide 95 in 53% yield over the two step sequence. Finally, cleavage of the carbonate unmasked the phenol to furnish ivacaftor (XV) in 96% yield.
- 7.7 Dissociation Constants
- 11.08, 1.5
- 7.8 Livertox Summary
- Ivacaftor, lumacaftor, tezacaftor and elexacaftor are orally available potentiators or correctors of the cystic fibrosis transmembrane conductance regulator (CFTR) that are used to treat patients with cystic fibrosis with specific mutations of the CFTR. Ivacaftor alone or in combination with lumacaftor or tezacaftor has been associated with low rate of transient serum enzyme elevations during treatment, but not with clinically apparent acute liver injury with jaundice, while the addition of elexacaftor to ivacaftor and tezacaftor has been implicated in a higher rate of serum enzyme elevations (up to 10% of patients) and to rare instances of clinically apparent liver injury with jaundice.
- 7.9 Drug Classes
- Cystic Fibrosis Agents
- 7.10 Mesh
- A class of drugs that stimulate chloride ion influx through cell membrane channels. (See all compounds classified as Chloride Channel Agonists.)
- 7.11 Absorption
- Ivacaftor is well absorbed in the gastrointestinal tract. Following administration of ivacaftor with fat-containing foods, peak plasma concentrations were reached at 4 hours (Tmax) with a maximum concentration (Cmax) of 768 ng/mL and AUC of 10600 ng * hr/mL. It is recommended that ivacaftor is taken with fat-containing foods as they increase absorption by approximately 2.5- to 4-fold.|After oral administration, ivacaftor is mainly eliminated in the feces after metabolic conversion and this elimination represents 87.8% of the dose. From the total eliminated dose, the metabolites M1 and M6 account for the majority of the eliminated dose, being 22% for M1 and 43% for M6. Ivacaftor shows negligible urinary excretion as the unchanged drug.|After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.|The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
- 7.12 Metabolism
- Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. From this metabolism, the major formed metabolites are M1 and M6. M1 is considered pharmacologically active even though it just presents approximately one-sixth the effect of the parent compound ivacaftor. On the other hand, M6 is not considered pharmacologically active as it represents less than one-fiftieth of the effect of the parent compound.
- 7.13 Biological Half Life
- In a clinical study, the apparent terminal half-life was approximately 12 hours following a single dose of ivacaftor. One source mentions the half-life ranges from 12 to 14 hours.
- 7.14 Mesh Entry Terms
- 3-quinolinecarboxamide, N-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-1,4-dihydro-4-oxo-
- 7.15 Use Classification
- Human drugs -> Orkambi -> EMA Drug Category|Other respiratory system products -> Human pharmacotherapeutic group|Human drugs -> Orphan -> Kalydeco -> EMA Drug Category|Human drugs -> Orphan -> Symkevi -> EMA Drug Category|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human drugs -> Orphan -> Kaftrio -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
- 7.16 Uses
- Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively
- 7.17 Uses
- Ivacaftor is used in the treatment of cystic fibrosis.
- 7.18 Definition
- ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with the amino group of 5-amino-2,4-di-tert-butylphenol. Used for the treatment of cystic fibrosis.
8. Computational chemical data
- Molecular Weight: 392.49g/mol
- Molecular Formula: C24H28N2O3
- Compound Is Canonicalized: True
- XLogP3-AA: 5.6
- Exact Mass: 392.20999276
- Monoisotopic Mass: 392.20999276
- Complexity: 671
- Rotatable Bond Count: 4
- Hydrogen Bond Donor Count: 3
- Hydrogen Bond Acceptor Count: 4
- Topological Polar Surface Area: 78.4
- Heavy Atom Count: 29
- Defined Atom Stereocenter Count: 0
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADceB7MAAAAAAAAAAAAAAAAAAAAAAAAAAwYIAAAAAAAACBQAAAHgAQCAAADgzBmAQyxoLAAgCIAqVWUACCAAAlIgAIiIEObMgIJjrKlZOEcYhm1BnI2ceY2fOfqAACAgAKAABQAAQEABQAAAAAAAAAAA==
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Ivacaftor
- Purity:99%Packing: 200kg/bag FOB
- Price: 1 USD/kilogram
- Time: 2019/05/21
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VX-770
- Purity:99%Packing: 200kg/bag FOB
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- Time: 2017/05/24
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