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| Targets |
CFTR corrector 8 specifically targets the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It functions as a CFTR corrector, which means its mechanism is to bind to the defective CFTR protein and assist in its proper folding and trafficking. By facilitating the movement of CFTR to the cell surface, it aims to restore the function of the chloride channel..
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| ln Vitro |
Compound 12, or CFTR corrector 8, has EC50 values of 1 μM in the CSE-HRP assay and 3 μM in the HBE-TECC assay [1]. Hepatocyte clearance rate for CFTR corrector 8 is 1250/775 L/hr/kg (human/rat)[1].
In vitro, CFTR corrector 8 demonstrates notable correction activity. It shows EC50 values of 1 microM in the CSE-HRP assay and 3 microM in the HBE-TECC assay (measuring CFTR function in human bronchial epithelial cells).. The compound also exhibits specific pharmacokinetic properties, with a hepatocyte clearance rate of 1250 L/hr/kg in humans and 775 L/hr/kg in rats, indicating it may be a high-clearance compound processed by the liver.. |
| ln Vivo |
Specific in vivo activity data for CFTR corrector 8 has not been detailed in the provided search results. However, as a highly effective CFTR modulator, its in vivo efficacy would be evaluated in an animal model of cystic fibrosis (such as a CFTR knockout mouse or a rat with a humanized CFTR mutation). Endpoints would include measuring CFTR-dependent chloride secretion in the intestine using Ussing chambers or measuring nasal potential difference (NPD), a clinical biomarker. Histological analysis of lung tissue and survival studies would also be key measures of efficacy.
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| Enzyme Assay |
CFTR corrector 8 functions to correct the folding and trafficking of the CFTR protein. Its primary activity is not mediated by binding to an isolated enzyme in a test tube. Instead, the most effective cell-free approach is to use an ATPase activity assay on purified CFTR protein reconstituted into liposomes. The activity of the purified CFTR is measured by quantifying the amount of inorganic phosphate (Pi) released from ATP hydrolysis in the presence of the test compound. However, this method is complex. Therefore, the primary data for CFTR corrector 8 comes from functional cell-based assays.
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| Cell Assay |
The in vitro cellular assay for CFTR corrector 8 typically involves using either CSE-HRP (a cellular assay using CFTR-expressing cells) or HBE-TECC (an assay using primary human bronchial epithelial cells derived from CF patients). These cell types are cultured in specialized plates and treated with varying concentrations of CFTR corrector 8 (from 1 nM to 100 uM) for 24-48 hours. After treatment, CFTR function is measured by adding a chloride-sensitive fluorescent probe or by using the halide-sensitive YFP (HS-YFP) quenching assay. Cells are exposed to an iodide (I-) gradient, and the rate of fluorescence decay is recorded. The EC50 values (1 microM and 3 microM, respectively) are calculated from the resulting dose-response curves..
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| Animal Protocol |
An in vivo protocol for CFTR corrector 8 would typically use a CFTR knockout mouse model (e.g., Cftrtm1Unc) or a transgenic rat expressing the human F508del-CFTR mutation. The compound is administered by oral gavage at doses ranging from 10 to 100 mg/kg, once or twice daily for 1-4 weeks. The primary efficacy endpoint is the measurement of CFTR-mediated chloride secretion in the intestinal tract using a Ussing chamber (short-circuit current). Secondary endpoints include improvement in weight gain, reduction in intestinal obstruction, histological analysis of lung and intestinal tissues, and survival studies.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for CFTR corrector 8 indicates that it has a high clearance rate. The hepatocyte clearance rate is reported as 1250 L/hr/kg in humans and 775 L/hr/kg in rats.. This high clearance suggests that the compound is rapidly metabolized by the liver. As a research compound, it is solubilized in DMSO (50 mg/mL) for in vitro studies and could be formulated for in vivo use with a vehicle such as 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O. Its half-life would be relatively short, requiring frequent dosing in animal models if systemic exposure is desired.
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| Toxicity/Toxicokinetics |
Specific toxicological data for CFTR corrector 8 is not available. Standard safety screening for a CFTR corrector would include an in vitro cytotoxicity assay (e.g., MTT assay) on primary human bronchial epithelial cells to determine the maximum non-toxic concentration. A CYP450 (cytochrome P450) inhibition panel would be performed to assess potential drug-drug interactions, given its high hepatocyte clearance. In vivo, a 14-day repeat-dose oral toxicity study in rats would be required to determine the maximum tolerated dose (MTD) and the no-observed-adverse-effect level (NOAEL).
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| References | |
| Additional Infomation |
CFTR corrector 8 is a research-grade compound and is not approved for clinical use. It is a highly effective modulator of the CFTR protein, specifically designed for research related to cystic fibrosis.. It is a useful tool for studying the pathophysiology of cystic fibrosis and for the development of new therapies that aim to correct the fundamental defect of the disease. Its molecular weight is 539.52, and its structure is derived from the CFTR corrector ABBV/GLPG-2222..
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| Molecular Formula |
C29H27F2NO7
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| Molecular Weight |
539.523995637894
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| Exact Mass |
539.175
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| CAS # |
1918142-35-4
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| PubChem CID |
121301422
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| Appearance |
Off-white to pink solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
39
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| Complexity |
888
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1(OC2=CC=C(C=C2O1)C1(C(N[C@@H]2C3C=CC(=CC=3O[C@H](C3C=CC(=C(C=3)OC)OC)C2)OC)=O)CC1)F
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| InChi Key |
KDOQEEMQPHIANX-REWPJTCUSA-N
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| InChi Code |
InChI=1S/C29H27F2NO7/c1-34-18-6-7-19-20(15-23(37-24(19)14-18)16-4-8-21(35-2)25(12-16)36-3)32-27(33)28(10-11-28)17-5-9-22-26(13-17)39-29(30,31)38-22/h4-9,12-14,20,23H,10-11,15H2,1-3H3,(H,32,33)/t20-,23-/m0/s1
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| Chemical Name |
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4S)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropane-1-carboxamide
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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: 110 mg/mL (203.88 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8535 mL | 9.2675 mL | 18.5350 mL | |
| 5 mM | 0.3707 mL | 1.8535 mL | 3.7070 mL | |
| 10 mM | 0.1853 mL | 0.9267 mL | 1.8535 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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