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873054-44-5 molecular structure
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N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

ChemBase ID: 72540
Molecular Formular: C24H28N2O3
Molecular Mass: 392.49072
Monoisotopic Mass: 392.20999277
SMILES and InChIs

SMILES:
c1c(c(cc(c1C(C)(C)C)NC(=O)c1c(=O)c2c([nH]c1)cccc2)O)C(C)(C)C
Canonical SMILES:
O=C(c1c[nH]c2c(c1=O)cccc2)Nc1cc(O)c(cc1C(C)(C)C)C(C)(C)C
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

Cite this record

CBID:72540 http://www.chembase.cn/molecule-72540.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
IUPAC Traditional name
ivacaftor
Synonyms
VX-770
CAS Number
873054-44-5
PubChem SID
162037465
PubChem CID
16220172

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1144 external link Add to cart Please log in.
Data Source Data ID
PubChem 16220172 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 6.569558  H Acceptors
H Donor LogD (pH = 5.5) 5.7243476 
LogD (pH = 7.4) 4.992087  Log P 5.7580223 
Molar Refractivity 118.683 cm3 Polarizability 43.880188 Å3
Polar Surface Area 78.43 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Storage Condition
-20°C expand Show data source
Target
CFTR expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1144 external link
Research Area
Description Cancer
Biological Activity
Description Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively.
Targets G551D-CFTR F508del-CFTR
IC50 100 nM 25 nM [1]
In Vitro Ivacaftor (10 μM) significantly increases the forskolin-stimulated Cl- secretion (IT) by ~4-fold with an EC50 of 100 nM in the recombinant Fisher rat thyroid (FRT) cells expressing G551D gating mutation of CFTR, and by ~6-fold with an EC50 of 25 nM in the recombinant cells expressing temperature-corrected F508del processing mutation of CFTR. Consistent with the increases in the forskolin-stimulated IT, Ivacaftor (10 μM) increases the open probability (Po) of G551D-, F508del-, and wild-type CFTR by ~6-fold, ~5-fold and ~2-fold, respectively, indicating that Ivacaftor acts directly on CFTR to increase its gating activity. In primary cultured human CF bronchial epithelia (HBE) carrying the G551D and F508del CFTR mutations, Ivacaftor (10 μM) potently increases the forskolin-stimulated IT by ~10-fold from 5% to a maximum level of 48% of that measured in non-CF HBE, with an EC50 of 236 nM displaying ~70-fold more potency compared with the commonly used CFTR potentiator genistein, which has an EC50 of 16 μM. In HBE with F508del homozygous CFTR, Ivacaftor causes a significant increase in the forskolin-stimulated IT with an EC50 of 22 nM, to a less extent from 4% to 16% of non-CF HBE compared with the effect in G551D/F508del HBE. Due to CFTR potentiation, Ivacaftor inhibits excessive ENaC-mediated Na+ and fluid absorption with an IC50 of 43 nM, and decreases the amiloride response, resulting in an increase in the surface fluid and cilia beat frequency (CBF) in G551D/F508del HBE. [1]
In Vivo
Clinical Trials A Phase III study of Ivacaftor in cystic fibrosis subjects age 6 to 11 with the G551D mutation has been completed.
Features Ivacaftor is the first potent and orally available CFTR potentiator to enter human clinical trials.
Protocol
Kinase Assay [1]
Ussing Chamber Recordings The effect of Ivacaftor on CFTR-mediated Cl- secretion is characterized by measuring the CFTR-mediated IT in chambers using recombinant Fisher rat thyroid (FRT) cells expressing G551D, or F508del CFTR. Cells are grown on Costar Snapwell cell culture inserts maintained at 37 °C before recording. The cell culture inserts are mounted into an Ussing chamber to record IT in the voltage-clamp mode (Vhold = 0 mV). For FRT cells, the basolateral membrane is permeabilized with 360 μg/mL Nystatin and a basolateral to apical Cl- gradient is established. The basolateral bath solution contains 135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KHPO4, 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes), and 10 mM dextrose (titrated to pH 7.4 with NaOH). The apical NaCl is replaced by equimolar Na+ gluconate (titrated to pH 7.4 with NaOH). The addition of a maximally effective concentration of forskolin (10 μM) is used to stimulate IT in the presence of various concentrations of Ivacaftor. All recordings are digitally acquired using Acquire and Analyze software. EC50 values are determined from the concentration-response curve of the increase in forskolin-stimulated IT after application of Ivacaftor.
References
[1] Van Goor F, et al. Proc Natl Acad Sci U S A, 2009, 106(44), 18825-18830.

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