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| Targets |
CFTR corrector 6 specifically targets the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It acts as a CFTR potentiator, a type of modulator that enhances the channel's function once it is present at the cell surface.. By binding to and stabilizing the open conformation of the channel, it increases chloride ion conductance, which is the primary therapeutic goal for restoring airway surface liquid hydration in CF..
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| ln Vitro |
For primary cystic fibrosis human bronchial epithelial (CF hBE) cells and fischer rat thyroid (FRT) cell lines, CFTR corrector 6 (Example 27) shows EC50s of 1.25 nM and 1.27 nM[1].
In vitro, CFTR corrector 6 (Example 27) is highly potent. It demonstrates EC50 values of 1.25 nM and 1.27 nM in primary cystic fibrosis human bronchial epithelial (CF hBE) cells and Fischer rat thyroid (FRT) cell lines, respectively.. These values indicate its ability to restore CFTR-mediated chloride transport at sub-nanomolar concentrations, which classifies it as a very high-affinity potentiator.. |
| ln Vivo |
Specific in vivo activity data for CFTR corrector 6 has not been detailed in the provided search results. However, as a highly potent CFTR potentiator, its in vivo efficacy would be assessed in a relevant animal model of CF (e.g., CFTR knockout mice expressing a human CFTR mutation) by measuring improvements in chloride transport and reducing the pathophysiology associated with the disease.
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| Enzyme Assay |
CFTR corrector 6 is a CFTR potentiator, which works by increasing the activity of CFTR channels already present at the cell surface. Its function is not mediated through a classical enzyme or receptor binding, but through direct allosteric modulation of the channel. In vitro, its activity is measured by assessing its ability to enhance the channel open probability using electrophysiological techniques (e.g., patch clamp). However, no specific cell-free binding assay for this compound is detailed in the search results.
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| Cell Assay |
The in vitro cellular assay for CFTR corrector 6 (Example 27) involves the use of Fischer rat thyroid (FRT) cells stably expressing the F508del-CFTR mutation. Cells are cultured in 96-well plates and pre-incubated with the compound to allow for accumulation and action on the channel. After pre-incubation, CFTR-mediated chloride transport is measured using a fluorescence-based plate reader in a halide-sensitive yellow fluorescent protein (HS-YFP) quenching assay. The rate of fluorescence decay reflects CFTR ion channel activity, and EC50 values are calculated to determine the compound's potency..
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| Animal Protocol |
An in vivo protocol for evaluating a CFTR potentiator like corrector 6 would typically use a CFTR knockout mouse model (such as the CFTR-/- mouse) that has been genetically engineered to express the human F508del-CFTR mutation. The compound would be administered by oral gavage at varying doses (e.g., 0.1-10 mg/kg) daily for 1-2 weeks. The primary efficacy endpoint would be the measurement of CFTR-dependent chloride secretion in the intestinal tract using Ussing chamber technology (short-circuit current). Additional endpoints could include improvements in survival, weight gain, and reduction of intestinal obstruction (meconium ileus equivalent).
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| ADME/Pharmacokinetics |
Comprehensive pharmacokinetic data for CFTR corrector 6 is limited. As a small molecule with a molecular weight of 479.39 g/mol, it is likely designed for oral administration.. For research purposes, it is solubilized in DMSO for in vitro work and can be formulated for in vivo applications. Its hepatocyte clearance rate is reported as 1250 L/hr/kg in humans and 775 L/hr/kg in rats., indicating it may be a high-clearance compound metabolized by the liver.
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| Toxicity/Toxicokinetics |
Specific toxicological data for CFTR corrector 6 is not available. Standard safety screening for CFTR modulators would include an in vitro hERG (human Ether-à-go-go-Related Gene) channel inhibition test to assess the potential for cardiotoxicity. A broad panel of off-target receptor screening (e.g., CEREP) would be conducted to confirm target specificity. In vivo, a 14-28 day repeat-dose oral toxicity study in rats would be performed to determine the Maximum Tolerated Dose (MTD) and No Observed Adverse Effect Level (NOAEL).
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| References | |
| Additional Infomation |
CFTR corrector 6 is a research-grade compound and is not approved for clinical use. It is categorized as a highly effective CFTR potentiator and is used in basic research to study CFTR biology and for the development of new cystic fibrosis therapies. It is covered by patent WO2018094137A1.. This compound is a critical tool for investigating the pharmacology of CFTR potentiation, particularly for understanding the structure-activity relationships of highly potent modulators. It is for research use only.
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| Molecular Formula |
C22H13F4N9
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|---|---|
| Molecular Weight |
479.39
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| Exact Mass |
479.123
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| CAS # |
2226970-01-8
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| PubChem CID |
134518643
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| Appearance |
White to off-white solid powder
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| LogP |
2.8
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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 |
4
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| Heavy Atom Count |
35
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| Complexity |
783
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(C=C(C=N1)CN1C(C#N)=C(C2=CN=C(C(F)(F)F)N=C2)C2=C1N=CN=C2N)C1C=CC=CC=1F
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| InChi Key |
LSTMAJPRFFZYIT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H13F4N9/c23-14-3-1-2-4-15(14)35-10-12(6-33-35)9-34-16(5-27)17(18-19(28)31-11-32-20(18)34)13-7-29-21(30-8-13)22(24,25)26/h1-4,6-8,10-11H,9H2,(H2,28,31,32)
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| Chemical Name |
4-amino-7-[[1-(2-fluorophenyl)pyrazol-4-yl]methyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 100 mg/mL (208.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.21 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0860 mL | 10.4299 mL | 20.8598 mL | |
| 5 mM | 0.4172 mL | 2.0860 mL | 4.1720 mL | |
| 10 mM | 0.2086 mL | 1.0430 mL | 2.0860 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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