| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
CFTR/cystic fibrosis transmembrane conductance regulator
Olacaftor targets the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It acts as a CFTR corrector, which means it enhances the processing and trafficking of the defective CFTR protein to the cell surface, thereby increasing the quantity of functional CFTR protein at the plasma membrane. This mechanism is particularly relevant for mutations like F508del that cause misfolding and premature degradation of the CFTR protein. |
|---|---|
| ln Vitro |
In vitro studies demonstrate that Olacaftor (VX-440) acts as a CFTR corrector, showing the potential to increase the amount of CFTR protein on the cell surface. As a next-generation corrector, it is designed to improve the processing and trafficking of mutant CFTR, thereby enhancing chloride transport in epithelial cells. Its in vitro activity is typically assessed using cell-based assays that measure CFTR-mediated ion transport in cells expressing specific CFTR mutations.
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| ln Vivo |
Olacaftor (VX-440) a next generation corrector was assessed in a phase 2 trial, randomized, double blind, placebo, and active-controlled study designed to evaluate the safety and tolerability of VX-440 in triple combination with tezacaftor and ivacaftor in patients with CF who are heterozygous for the F508del mutation and a MF CFTR mutation not likely to respond to tezacaftor and/or ivacaftor therapy (F508del-MF), or who are homozygous for the F508del mutation (ClinicalTrials.gov Identifier: NCT02951195)[https://pmc.ncbi.nlm.nih.gov/articles/PMC7088950/].
In vivo activity of Olacaftor is evaluated in animal models of cystic fibrosis, where it demonstrates the ability to improve CFTR function and reduce disease phenotypes. As a CFTR modulator, it is designed to enhance the function of the defective CFTR protein in vivo. The compound is typically administered orally, and its efficacy is measured by assessing improvements in chloride transport and reductions in lung pathology in preclinical models. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (cell-free) assay for Olacaftor typically involves binding studies to assess its interaction with the CFTR protein. These assays may use purified CFTR protein or membrane preparations to measure direct binding affinity. However, as a CFTR corrector, its primary mechanism involves improving protein processing rather than direct receptor binding, so cell-free assays may focus on biochemical interactions that stabilize the CFTR protein during its folding and maturation process.
|
| Cell Assay |
In vitro cellular assays for Olacaftor are performed using cell lines expressing mutant CFTR, such as those with the F508del mutation. These assays measure CFTR-mediated chloride transport using techniques like Ussing chamber analysis or fluorescent membrane potential assays. The compound's ability to increase cell surface expression of CFTR is also assessed via biochemical methods such as Western blotting and cell surface biotinylation. These assays demonstrate the corrector activity of Olacaftor in enhancing CFTR function.
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| Animal Protocol |
In vivo animal studies for Olacaftor are conducted in CFTR-deficient mouse models or other relevant animal models of cystic fibrosis. These studies typically involve oral administration of the compound, followed by assessment of CFTR function in various tissues, particularly the lungs and intestines. Efficacy endpoints may include measurements of chloride transport, assessments of lung pathology, and improvements in survival or weight gain. Pharmacodynamic markers are also evaluated to confirm target engagement.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Olacaftor are characteristic of a small molecule CFTR modulator designed for oral administration. It is typically formulated for systemic delivery and undergoes standard absorption, distribution, metabolism, and excretion (ADME) processes. As a next-generation corrector, it is optimized for improved bioavailability and pharmacokinetic profile compared to earlier compounds. Detailed PK parameters such as half-life, Cmax, and AUC are determined in preclinical species and clinical studies.
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| Toxicity/Toxicokinetics |
Toxicology studies of Olacaftor are conducted to evaluate its safety profile in preclinical species. These studies include acute and repeat-dose toxicity assessments, as well as genotoxicity and safety pharmacology evaluations. As a CFTR modulator intended for chronic use in cystic fibrosis patients, extensive toxicology testing is required to establish a safety margin for clinical use. The compound is generally well-tolerated in preclinical studies at therapeutic doses.
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| References | |
| Additional Infomation |
Olacaftor is being investigated in the clinical trial NCT02951182 (a study evaluating the safety and efficacy of VX-440 in combination therapy in patients with cystic fibrosis).
Olacaftor, also known as VX-440, is a next-generation CFTR corrector developed for the treatment of cystic fibrosis. It is part of a class of CFTR modulators that include correctors, potentiators, and stabilizers. The compound has been investigated in combination with other CFTR modulators to achieve synergistic effects in patients with specific CFTR mutations. Clinical trials have explored its use in various CF patient populations, particularly those with the F508del mutation. |
| Molecular Formula |
C29H34FN3O4S
|
|---|---|
| Molecular Weight |
539.6664
|
| Exact Mass |
539.225
|
| Elemental Analysis |
C, 64.54; H, 6.35; F, 3.52; N, 7.79; O, 11.86; S, 5.94
|
| CAS # |
1897384-89-2
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| Related CAS # |
(R)-Olacaftor;1899111-41-1
|
| PubChem CID |
121250885
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| Appearance |
White to yellow solid powder
|
| Density |
1.2±0.1 g/cm3
|
| Index of Refraction |
1.563
|
| LogP |
6.43
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
38
|
| Complexity |
902
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
C[C@H]1CC(N(C1)C2=C(C=CC(=N2)C3=CC(=CC(=C3)F)OCC(C)C)C(=O)NS(=O)(=O)C4=CC=CC=C4)(C)C
|
| InChi Key |
NHOUNZMCSIHKHJ-FQEVSTJZSA-N
|
| InChi Code |
InChI=1S/C29H34FN3O4S/c1-19(2)18-37-23-14-21(13-22(30)15-23)26-12-11-25(27(31-26)33-17-20(3)16-29(33,4)5)28(34)32-38(35,36)24-9-7-6-8-10-24/h6-15,19-20H,16-18H2,1-5H3,(H,32,34)/t20-/m0/s1
|
| Chemical Name |
N-(benzenesulfonyl)-6-[3-fluoro-5-(2-methylpropoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide
|
| Synonyms |
VX 440; VX-440; 1897384-89-2; Olacaftor [USAN]; VX-440; RZ7027HK8F; UNII-RZ7027HK8F; OLACAFTOR [INN]; Olacaftor (USAN); Olacaftor
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~92.65 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.62 mg/mL (1.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.62 mg/mL (1.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8530 mL | 9.2649 mL | 18.5298 mL | |
| 5 mM | 0.3706 mL | 1.8530 mL | 3.7060 mL | |
| 10 mM | 0.1853 mL | 0.9265 mL | 1.8530 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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