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| Targets |
COX-2
Cyclooxygenase-2 (COX-2). COX-2-IN-6 is an orally active, gut-restricted, and selective COX-2 inhibitor. It selectively targets COX-2 with an IC50 of 0.84 μM and a Ki of 69 nM. The compound is selective for COX-2 over COX-1 (IC50 = >50 μM). By blocking COX-2 enzymatic activity, it reduces the synthesis of pro-inflammatory prostaglandins, thereby modulating pain, fever, and inflammatory responses. |
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| ln Vitro |
With an IC50 of 0.84 μM, >50 μM, and 0.60 μM, respectively, COX-2-IN-6 (Compound 10) inhibits the human COX-2/COX-1 enzyme and COX-2/COX-1-driven PGE2 synthesis in HEK293 cells. and greater than 50 μM[1]. In vitro, COX-2-IN-6 demonstrates stability in hepatocytes and human or mouse liver microsomes. Human hepatocytes have a T1/2 value of 3.1 minutes, while mouse hepatocytes have a T1/2 value of 3.0 minutes[1].
COX-2-IN-6 selectively inhibits COX-2 with an IC50 of 0.84 μM and a Ki of 69 nM. It is selective for COX-2 over COX-1 (IC50 = >50 μM). The compound inhibits COX-2-driven PGE2 synthesis with an IC50 of 0.60 μM. These in vitro activities demonstrate the compound's potent and selective inhibition of COX-2, making it a valuable tool for studying COX-2-mediated inflammation and carcinogenesis. |
| ln Vivo |
In the APCmin/+ mouse model, COX-2-IN-6 (Compound 10) (30-300 mg/kg; oral; single dosage) slows the evolution of adenoma and increases survival[1]. With a C/P distribution ratio of more than 1200 in 4 hours, COX-2-IN-6 (10 mg/kg; oral; single dose) shows substantial colonic exposure (>4300 ng/g) and minimal systemic exposure (<6 ng/mL)[1].
In vivo, COX-2-IN-6 (300 mg/kg) selectively accumulates in the colon versus the plasma. This gut-restricted distribution reduces systemic exposure and potential side effects associated with systemic COX-2 inhibition. The compound's oral activity and colon-selective accumulation make it a promising candidate for colorectal cancer chemoprevention. The compound's ability to inhibit COX-2-driven PGE2 synthesis in the colon may reduce inflammation-driven carcinogenesis. |
| Enzyme Assay |
Enzyme activity assays are used to measure the inhibitory activity of COX-2-IN-6 against COX-1 and COX-2. Purified recombinant COX-1 and COX-2 enzymes are incubated with arachidonic acid substrate in the presence of increasing concentrations of the compound. Prostaglandin production is measured by ELISA or radiometric assays to determine IC50 values. The reported IC50 for COX-2 is 0.84 μM, with a Ki of 69 nM. Selectivity over COX-1 is demonstrated by IC50 >50 μM.
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| Cell Assay |
Cellular assays using COX-2-expressing cells are employed to evaluate the functional inhibition of COX-2-IN-6. HEK293 cells expressing COX-2 or COX-1 are treated with increasing concentrations of the compound, and PGE2 production is measured by ELISA. The compound inhibits PGE2 production in COX-2-expressing cells with an IC50 of 0.60 μM, while showing no significant inhibition in COX-1-expressing cells (IC50 >50 μM). This confirms the compound's cellular selectivity for COX-2.
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| Animal Protocol |
Animal/Disease Models: APCmin/+ mouse model[1]
Doses: 30 mg/kg, 100 mg/kg, 300 mg/kg Route of Administration: PO; daily in chow diet Experimental Results: Dramatically diminished [18F]-FDG uptake and polyp area. In vivo efficacy of COX-2-IN-6 has been evaluated in preclinical models of colorectal cancer. The compound is administered orally at doses such as 300 mg/kg, and its tissue distribution is assessed. Efficacy endpoints include reduction of colonic PGE2 levels, inhibition of aberrant crypt foci formation, and reduction of tumor burden in carcinogen-induced or genetically engineered mouse models of colorectal cancer. The gut-restricted property is confirmed by measuring compound levels in colon versus plasma. |
| ADME/Pharmacokinetics |
As an orally active small molecule with molecular weight of 393.5 g/mol and molecular formula C20H27NO6S, COX-2-IN-6 is administered orally in animal studies. The compound's gut-restricted property results in selective accumulation in the colon versus plasma, reducing systemic exposure. It is soluble in ethanol (≥10 mg/ml) and sparingly soluble in DMSO (1-10 mg/ml). The compound is stored at -20°C and shipped at room temperature.
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| Toxicity/Toxicokinetics |
No specific toxicity data has been reported for COX-2-IN-6. The gut-restricted design aims to reduce systemic toxicities associated with COX-2 inhibitors, such as cardiovascular and renal effects. Standard toxicity assessments would include evaluation of gastrointestinal, cardiovascular, and renal toxicity in animal models. The compound is for research use only and not intended for human therapeutic use.
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| References |
[1]. Zhang Z, et al. Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer. J Med Chem. 2021 Aug 12;64(15):11570-11596.
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| Additional Infomation |
COX-2-IN-6 (CAS#: 2756347-91-6) is a gut-restricted, orally active, and selective COX-2 inhibitor for colorectal cancer chemoprevention. It selectively targets COX-2 with an IC50 of 0.84 μM and a Ki of 69 nM, and is selective over COX-1 (IC50 >50 μM). It inhibits COX-2-driven PGE2 synthesis with an IC50 of 0.60 μM. In vivo, COX-2-IN-6 selectively accumulates in the colon versus plasma. Molecular formula: C20H27NO6S. CAS: 2756347-91-6.
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| Molecular Formula |
C20H27NO6S
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| Molecular Weight |
409.496484994888
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| Exact Mass |
409.155
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| CAS # |
2756347-91-6
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| PubChem CID |
156587566
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
28
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| Complexity |
568
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCOC1=NC(=C(C=C1CO)C2=CC=C(C=C2)S(=O)(=O)C)OCC(C)(C)O
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| InChi Key |
MIGCLPHEGAEITL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H27NO6S/c1-5-10-26-18-15(12-22)11-17(19(21-18)27-13-20(2,3)23)14-6-8-16(9-7-14)28(4,24)25/h6-9,11,22-23H,5,10,12-13H2,1-4H3
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| Chemical Name |
1-[5-(hydroxymethyl)-3-(4-methylsulfonylphenyl)-6-propoxypyridin-2-yl]oxy-2-methylpropan-2-ol
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (244.20 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 | 2.4420 mL | 12.2100 mL | 24.4200 mL | |
| 5 mM | 0.4884 mL | 2.4420 mL | 4.8840 mL | |
| 10 mM | 0.2442 mL | 1.2210 mL | 2.4420 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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