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Ivacaftor

Product Name
Ivacaftor
CAS No.
873054-44-5
Chemical Name
Ivacaftor
Synonyms
Ivacaftor;Kalydeco;Ivacaftor (VX-770);N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxaMide;N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide Ivacaftor (VX-770);CS-1914;Ivacato;Ivacaftor-D4;Ivacaftor D6;VX-770 vacaftor
CBNumber
CB32506174
Molecular Formula
C24H28N2O3
Formula Weight
392.49
MOL File
873054-44-5.mol
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Ivacaftor Property

Melting point:
212-215°C
Boiling point:
550.4±50.0 °C(Predicted)
Density 
1.187
storage temp. 
Refrigerator
solubility 
DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)
pka
11.08±0.23(Predicted)
form 
Solid
color 
White to Light Brown
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)
InChIKey
PURKAOJPTOLRMP-UHFFFAOYSA-N
SMILES
N1C2=C(C=CC=C2)C(=O)C(C(NC2=CC(O)=C(C(C)(C)C)C=C2C(C)(C)C)=O)=C1
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Safety

HS Code 
29333990
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

H361Suspected of damaging fertility or the unborn child

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P281Use personal protective equipment as required.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P308+P313IF exposed or concerned: Get medical advice/attention.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P362Take off contaminated clothing and wash before reuse.

P405Store locked up.

P501Dispose of contents/container to..…

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N-Bromosuccinimide Price

Sigma-Aldrich
Product number
5.30541
Product name
CFTR Potentiator, VX-770 - CAS 873054-44-5 - Calbiochem
Packaging
10mg
Price
$289
Updated
2023/01/07
Cayman Chemical
Product number
15145
Product name
Ivacaftor
Purity
≥98%
Packaging
1mg
Price
$33
Updated
2024/03/01
Cayman Chemical
Product number
15145
Product name
Ivacaftor
Purity
≥98%
Packaging
5mg
Price
$131
Updated
2024/03/01
Cayman Chemical
Product number
15145
Product name
Ivacaftor
Purity
≥98%
Packaging
10mg
Price
$245
Updated
2024/03/01
Cayman Chemical
Product number
15145
Product name
Ivacaftor
Purity
≥98%
Packaging
50mg
Price
$734
Updated
2024/03/01
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Ivacaftor Chemical Properties,Usage,Production

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.

Originator

Vertex Pharmaceuticals (United States)

Uses

Ivacaftor is used in the treatment of cystic fibrosis.

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

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.

brand name

Kalydeco

Mechanism of action

Ivacaftor is an oral agent that increases the ion-function of activated cell-surface CFTR. In vitro studies using bronchial epithelial cells from the lungs of patients with CF have demonstrated that increases in the air-surface fluid level and ciliary beat frequency can be obtained by correcting abnormal CFTR-mediated ion transport. Possible improvement in airway obstruction could occur by decreasing mucus plugging through better hydration of the airway surface and increased mucus clearance. Ivacaftor potentiates CFTR to restore chloride gating function in CFTR with class III gating defects, such as with the G551D variant[3-4].

Pharmacokinetics

Administered as an oral dose, ivacaftor absorbs readily from the gut but has low solubility in water (< 0.05 ug/mL). Taking a 150 mg dose of ivacaftor with a high-fat meal improves absorption, increases AUC by 2.5 times, and delays Tmax from 3 to 5 hours. Dose/time pharmacokinetics follows a linear profile to a dose of 250 mg, though Cmax plateaus for doses 375 mg and higher. Ivacaftor is transported in the plasma highly bound (99%), preferentially to alpha-1-acid glycoprotein and albumin, to its site of action, the apical membrane of epithelial cells. However, no drug-drug interactions related to protein binding competition are expected.

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.

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.

target

G551D-CFTR

Metabolism

Ivacaftor is metabolized in the liver by cytochrome P450 3A (CYP3A), including both CYP3A4 and CYP3A5, into a metabolite hydroxymethyl-ivacaftor (M1), which is considered to be active with a potency 1/6th that of ivacaftor itself, and the inactive metabolite ivacaftor-carboxylate (M6), which not considered active and has an activity level 1/50th that of ivacaftor. The parent drug and metabolites are eliminated predominantly (87%) through the bile, with 22% being the M1 metabolite and 43% being the M6 metabolite. The M6 metabolite is excreted in the bile through the solute carrier organic anion transporter 1B1 (SLCO1B1) transporter, but the mechanism for eliminating M1 is unknown. Ivacaftor has a half-life of 12–14 hours[3].

References

[1] van goor f1, hadida s, grootenhuis pd, burton b, cao d, neuberger t, turnbull a, singh a, joubran j, hazlewood a, zhou j, mccartney j,arumugam v, decker c, yang j, young c, olson er, wine jj, frizzell ra, ashlock m, negulescu p. rescue of cf airway epithelial cell function in vitro by a cftr potentiator, vx-770. proc natl acad sci u s a. 2009 nov 3;106(44):18825-30.
[2] vachel l1, norez c, becq f, vandebrouck c. effect of vx-770 (ivacaftor) and oag on ca2+ influx and cftr activity in g551d and f508del-cftr expressing cells. j cyst fibros. 2013 dec;12(6):584-91
[3] A. Fohner. “PharmGKB summary: ivacaftor pathway, pharmacokinetics/pharmacodynamics.” Pharmacogenetics and genomics 30 1 (2017): 39–42.
[4] Michelle E Condren, & Marquita D Bradshaw. “Ivacaftor: a novel gene-based therapeutic approach for cystic fibrosis.” Journal of Pediatric Pharmacology and Therapeutics 18 1 (2013): 8–13.

Ivacaftor Preparation Products And Raw materials

Raw materials

Preparation Products

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Ivacaftor Suppliers

Canada 1 China 247 India 15 United Kingdom 2 United States 19 Global 284
AdooQ BioScience, LLC
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Target molecule Corp.
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TargetMol Chemicals Inc.
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marketing@targetmol.com
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InvivoChem
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Cckinase, Inc.
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BOC Sciences
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Aladdin Scientific
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Cayman Chemical Company
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View Lastest Price from Ivacaftor manufacturers

BEIJING SJAR TECHNOLOGY DEVELOPMENT CO., LTD.
Product
Ivacaftor 873054-44-5
Price
US $0.00/g
Min. Order
1g
Purity
More Than 99%
Supply Ability
100kg/Month
Release date
2024-09-10
Zhuozhou Wenxi import and Export Co., Ltd
Product
Ivacaftor 873054-44-5
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-10
Zhuozhou Wenxi import and Export Co., Ltd
Product
Ivacaftor 873054-44-5
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-09

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  • Ivacaftor
  • Ivacaftor, >=98%
  • 3-QuinolinecarboxaMide, N-[2,4-bis(1,1-diMethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-
  • N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide Ivacaftor (VX-770)
  • N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide
  • N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxaMide
  • Ivacaftor (VX-770)
  • VX 770, Ivacaftor
  • Ivacaftor-D4
  • Kalydeco
  • VX-770(Ivacattor)
  • IVACAFTOR (VX-770);VX 770
  • N-(2,4-DITERT-BUTYL-5-HYDROXYPHENYL)-4-OXO-1H-QUINOLINE-3-CARBOXAMIDE
  • VX-770 vacaftor
  • KALYDECO;IVACAFTOR;VX770;VX 770
  • Ivacaftor Impurity
  • CS-1914
  • VX-770 ISO 9001：2015 REACH
  • N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquino...
  • VX-770, Ivacaftor, Kalydeco
  • Ivacaftor D6
  • IvacaftorQ: What is Ivacaftor Q: What is the CAS Number of Ivacaftor Q: What is the storage condition of Ivacaftor Q: What are the applications of Ivacaftor
  • CFTR Potentiator VX-770 Ivacaftor
  • 2,4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXAMID
  • Ivacato
  • Ivacaftor in methanol
  • 873054-44-5
  • 873054-44
  • 873055-44-5
  • API
  • Inhibitors