Ivacaftor Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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
(EC
50=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.
Verwenden
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.
Pharmakokinetik
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.
Ivacaftor Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
