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| Targets |
CFTR/cystic fibrosis transmembrane conductance regulator
(R)-Elexacaftor specifically targets the cystic fibrosis transmembrane conductance regulator (CFTR) protein. As a CFTR modulator and corrector, its mechanism involves binding to the defective CFTR protein to correct its processing and trafficking defects, allowing it to reach the cell surface as a functional chloride channel.. It is the R-enantiomer of the drug Elexacaftor, which is part of the triple-combination therapy Trikafta.. |
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| ln Vitro |
In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. [2]
In vitro, (R)-Elexacaftor demonstrates potent correction activity on the F508del CFTR mutant, which is the most common mutation causing cystic fibrosis. It exhibits an EC50 of 0.29 microM for CFTR dF508 (F508del-CFTR), indicating the concentration at which it restores 50% of the maximal CFTR-mediated chloride transport in a cell-based assay. This high potency (sub-micromolar range) makes it a highly effective CFTR corrector.. |
| ln Vivo |
In patients with cystic fibrosis, VX-445–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del–MF group (P<0.001). In patients in the Phe508del–Phe508del group, who were already receiving tezacaftor–ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised. CONCLUSIONS: The use of VX-445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients [2].
Specific in vivo activity data for (R)-Elexacaftor is not detailed in the search results. However, its parent compound Elexacaftor is clinically approved and has demonstrated robust efficacy in improving lung function (ppFEV1) and reducing sweat chloride levels in patients with CF. As the (R)-enantiomer, (R)-Elexacaftor likely exhibits similar or identical pharmacokinetic and pharmacodynamic properties, contributing to the in vivo efficacy observed for the racemate. |
| Enzyme Assay |
For a CFTR corrector, there is no single "receptor" to bind to in a classic cell-free assay; its activity is measured by its ability to increase the amount of CFTR protein at the cell surface. A standard method to assess this is a surface biotinylation assay. CFTR-expressing cells are treated with (R)-Elexacaftor for 24 hours, followed by cell surface labeling with a membrane-impermeable biotin reagent. Biotinylated proteins are captured on a streptavidin column, and the amount of CFTR protein pulled down is quantified by Western blotting using an anti-CFTR antibody. This cell-based assay provides the primary pharmacodynamic data for CFTR correctors.
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| Cell Assay |
The in vitro cellular assay to evaluate (R)-Elexacaftor's correction activity involves Fischer rat thyroid (FRT) cells that stably express the human F508del-CFTR mutation. The cells are seeded in 96-well plates and cultured at 37degC. After 24 hours, the cells are treated with varying concentrations of (R)-Elexacaftor (from 0.001 uM to 10 uM) for 24-48 hours to allow for protein correction and trafficking. Following incubation, CFTR channel function is measured using a fluorescence-based plate reader in a halide-sensitive yellow fluorescent protein (HS-YFP) quenching assay. Cells are exposed to an iodide gradient, and the rate of fluorescence decay, reflecting CFTR-mediated halide influx, is recorded. The EC50 value is calculated from the dose-response curve..
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| Animal Protocol |
An in vivo protocol for evaluating a CFTR corrector like (R)-Elexacaftor would involve a relevant animal model, such as the F508del-CFTR rat or a CFTR knockout mouse expressing human F508del-CFTR. The compound is administered by oral gavage at doses ranging from 1-30 mg/kg, typically once daily for 7-28 days. Primary efficacy endpoints include measuring CFTR-dependent chloride transport in the intestinal tract using Ussing chamber technology to calculate short-circuit current (Isc). Secondary endpoints involve improvements in survival, weight gain, and histological analysis of lung and intestinal tissues to assess disease pathology.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for (R)-Elexacaftor is not provided. However, its parent compound, Elexacaftor, is clinically administered and is well-absorbed orally. Standard PK parameters for Elexacaftor include a terminal half-life of approximately 15 hours, allowing for once-daily dosing. It is metabolized primarily by CYP3A enzymes in the liver and has moderate oral bioavailability. For research, (R)-Elexacaftor is typically dissolved in DMSO for in vitro experiments (100 mg/mL) and can be formulated for in vivo administration using a vehicle such as 10% DMSO/40% PEG300/5% Tween-80/45% saline..
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| Toxicity/Toxicokinetics |
Specific toxicological data for (R)-Elexacaftor is not available. The parent drug Elexacaftor has a well-established safety profile from clinical trials and post-marketing surveillance. Common adverse events associated with CFTR modulators include headache, nausea, diarrhea, and rash. The most serious but rare risk is drug-induced liver injury (DILI), requiring regular monitoring of liver function tests. In the clinic, the triple combination therapy (Trikafta) has an overall favorable safety profile. For research, in vitro safety screens would include an MTT cytotoxicity assay and a hERG channel inhibition test.
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| References |
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| Additional Infomation |
(R)-Elexacaftor is a research-grade compound and is not approved for clinical use as a single agent. It is the R-enantiomer of the CFTR corrector Elexacaftor (VX-445), which is an integral component of the FDA-approved drug Trikafta (elexacaftor/tezacaftor/ivacaftor). In the context of research, it is used to study the stereospecificity of CFTR modulation and the biological activity of individual enantiomers. Its molecular formula is C26H34F3N7O4S with a molecular weight of 597.65.. It is for research use only and not for human consumption.
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| Molecular Formula |
C26H34F3N7O4S
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|---|---|
| Molecular Weight |
597.652874469757
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| Exact Mass |
597.234
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| Elemental Analysis |
C, 52.25 H, 5.73 F, 9.54 N, 16.41 O, 10.71 S, 5.36
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| CAS # |
2229860-99-3
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| Related CAS # |
Elexacaftor;2216712-66-0
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| PubChem CID |
134587287
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| Appearance |
White to light yellow solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
41
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| Complexity |
1050
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C1=CN(C)N=C1C)(NC(C1=CC=C(N2C=CC(=N2)OCC(C)(C)C(F)(F)F)N=C1N1C[C@H](C)CC1(C)C)=O)(=O)=O
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| InChi Key |
MVRHVFSOIWFBTE-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C26H34F3N7O4S/c1-16-12-25(5,6)35(13-16)22-18(23(37)33-41(38,39)19-14-34(7)31-17(19)2)8-9-20(30-22)36-11-10-21(32-36)40-15-24(3,4)26(27,28)29/h8-11,14,16H,12-13,15H2,1-7H3,(H,33,37)/t16-/m1/s1
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| Chemical Name |
N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide
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| Synonyms |
(R)-Elexacaftor; 2229860-99-3; (R)-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide; VX-445 R enantiomer; SCHEMBL20239741; MVRHVFSOIWFBTE-MRXNPFEDSA-N;
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 125 mg/mL (209.15 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.48 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 20.8 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: ≥ 2.08 mg/mL (3.48 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 20.8 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 | 1.6732 mL | 8.3661 mL | 16.7322 mL | |
| 5 mM | 0.3346 mL | 1.6732 mL | 3.3464 mL | |
| 10 mM | 0.1673 mL | 0.8366 mL | 1.6732 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06331000 | Not yet recruiting | Drug: elexacaftor-tezacaftor-ivacaftor treatment |
Cystic Fibrosis | University Hospital, Strasbourg, France | March 2024 | |
| NCT05576324 | Recruiting | Drug: Elexacaftor / Ivacaftor / Tezacaftor | Cystic Fibrosis | University of Erlangen-Nürnberg Medical School |
December 30, 2020 | |
| NCT06184763 | Active, not recruiting | Other: 6-minute walk test | Cystic Fibrosis | Hospices Civils de Lyon | August 1, 2023 | |
| NCT06072365 | Completed | Other: nutritional intake questionnaire |
Cystic Fibrosis | University Hospital, Toulouse | October 21, 2021 |
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