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| Targets |
PTUPB targets two key enzymes: soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2). sEH is an enzyme that converts epoxy-fatty acids (EpFAs) to their corresponding diols. EpFAs, such as 11,12- and 14,15-epoxyeicosatrienoic acids (EETs), are endogenous lipid mediators with potent anti-inflammatory, analgesic, and vasodilatory properties. By inhibiting sEH, PTUPB prevents the degradation of EpFAs, leading to their accumulation and enhanced beneficial effects. COX-2 is an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, which are pro-inflammatory lipid mediators. By inhibiting COX-2, PTUPB reduces the production of prostaglandins, thereby decreasing inflammation and pain. The compound is highly selective for COX-2 over COX-1 (IC₅₀ >100 μM), which is important because COX-1 inhibition can lead to gastrointestinal and renal side effects. The dual inhibition of sEH and COX-2 by PTUPB provides a synergistic effect, as it simultaneously enhances anti-inflammatory pathways and blocks pro-inflammatory pathways.
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| ln Vitro |
PTUPB (1–10 μM; 24 hours) shows inhibitory efficacy against human 5-LOX, showing 83% and 44% inhibitory activity at 1 μM and 10 μM, respectively [1]. PTUPB (10-20) efficiently reduces the proliferation of HUVECs after 3 days of treatment, although it has negligible inhibitory effects on the proliferation of several blue lineages, including human melanoma cells and transformed endothelial cells [1]. Under varying conditions, μM; 72 hours) causes cell cycle induction in the G0/1 phase. PTUPB cell number percentages were 65.15%, 66.87%, and 65.91% at 10 μM, 15 μM, and 20 μM, respectively[1].
In vitro, PTUPB demonstrates potent inhibition of sEH and COX-2. It inhibits sEH with an IC₅₀ of 0.9 nM and COX-2 with an IC₅₀ of 1.26 μM. It does not inhibit COX-1 (IC₅₀ >100 μM). PTUPB also shows inhibitory efficacy against human 5-lipoxygenase (5-LOX), with 83% and 44% inhibitory activity at 1 μM and 10 μM, respectively. In cell-based assays, PTUPB (10-20 μM) efficiently reduces the proliferation of human umbilical vein endothelial cells (HUVECs) after 3 days of treatment, although it has negligible inhibitory effects on the proliferation of several cancer cell lines, including human melanoma cells and transformed endothelial cells. PTUPB (10-20 μM; 72 hours) induces cell cycle arrest in the G0/1 phase in HUVECs. The cell number percentages in G0/1 phase were 65.15%, 66.87%, and 65.91% at 10 μM, 15 μM, and 20 μM, respectively. These results indicate that PTUPB has anti-proliferative effects on endothelial cells, which may contribute to its anti-angiogenic and anti-tumor activities. |
| ln Vivo |
In comparison to heart rate, PTUPB (subcutaneous injection; 30 mg/kg; 4 weeks) reduced LLC tumor growth by 70–83% and showed no overt effects, such as weight loss. Following a course of treatment, peak plasma concentrations of PTUPB (subcutaneous injection; once daily; 5 mg/kg) improved non-alcoholic fatty liver disease caused by a high-fat diet by blocking the activation of the NLRP3 inflammasome. It can lower myocardial weight, body weight, and the expression of genes linked to nutrition. It can also break down fat or lipogenesis [2].
In vivo, PTUPB has demonstrated significant efficacy in several animal models. In a mouse model of LLC (Lewis lung carcinoma) tumor growth, subcutaneous injection of PTUPB (30 mg/kg; 4 weeks) reduced tumor growth by 70-83% and showed no overt effects, such as weight loss. In a high-fat diet (HFD)-induced obese mouse model, PTUPB (subcutaneous injection; once daily; 5 mg/kg) improved non-alcoholic fatty liver disease (NAFLD) by inhibiting the activation of the NLRP3 inflammasome. It reduced body weight, liver weight, hepatic triglyceride and cholesterol content, and the expression of genes linked to lipogenesis and lipid uptake. PTUPB also decreased inflammatory and oxidative stress markers in ZDF (Zucker diabetic fatty) rats. These in vivo results demonstrate that PTUPB has potent anti-inflammatory, anti-tumor, and metabolic effects. The compound's efficacy is attributed to its dual inhibition of sEH and COX-2, which leads to a reduction in inflammation and an improvement in metabolic parameters. |
| Enzyme Assay |
In a cell-free assay, sEH activity is measured using a fluorescent substrate. The assay is performed in a 96-well plate format. The reaction mixture contains 50 mM Tris-HCl buffer (pH 7.4), 0.1 mg/mL BSA, and the fluorescent substrate (e.g., (3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxy-naphthalen-2-yl)-methyl ester (PHOME)). The substrate is cleaved by sEH to release the fluorescent product, which is measured at excitation 330 nm and emission 465 nm. The reaction is initiated by the addition of the enzyme, and the increase in fluorescence is monitored over time. The percentage of inhibition at each compound concentration is calculated relative to a control without inhibitor. The IC₅₀ is determined by fitting the data to a four-parameter logistic model. For COX-2 inhibition, a similar cell-free assay is performed using a COX-2 enzyme and arachidonic acid as the substrate. The production of prostaglandin E₂ (PGE₂) is measured using an enzyme immunoassay (EIA). The IC₅₀ is determined from the dose-response curve. The selectivity for COX-2 over COX-1 is assessed using the same assay with COX-1 enzyme.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: Multiple cancer Cell Types: PC-3 cells, Met-1, H-1, A375, and transformed endothelial cell line (bEnd.3) Tested Concentrations: 10 μM, 15 μM and 20 μM Incubation Duration: 72 hour Experimental Results: Inhibited HUVEC proliferation after 3 days. Cell cycle analysis[1] Cell Types: HUVEC Tested Concentrations: 10 μM, 15 μM and 20 μM Incubation Duration: 72 hrs (hours) Experimental Results: Induced cell cycle arrest in G0/1 phase. For in vitro cellular assays, the anti-inflammatory and anti-proliferative effects of PTUPB are typically assessed using various cell lines. For inflammation assays, macrophages (e.g., RAW 264.7 cells) are stimulated with lipopolysaccharide (LPS) to induce an inflammatory response. The cells are treated with PTUPB at various concentrations (e.g., 0.1-10 μM) for 24 hours. The levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the culture medium are measured using ELISA. The levels of prostaglandin E₂ (PGE₂) are also measured to assess COX-2 inhibition. For cell proliferation assays, HUVECs or cancer cell lines are seeded in 96-well plates and treated with PTUPB at various concentrations (e.g., 1-20 μM) for 72 hours. Cell viability is assessed using an MTT or resazurin assay. Cell cycle analysis is performed by flow cytometry using propidium iodide staining. These assays provide a measure of the compound's anti-inflammatory and anti-proliferative activities in a cellular context. |
| Animal Protocol |
Animal/Disease Models: C57BL/6 mice with LLC cells [1]
Doses: 30 mg/kg; triglyceride and cholesterol content. 4-week dosing: subcutaneous injection via Alzet mini-osmotic pump; one time/day; 4-week Experimental Results: Inhibition of LLC tumor growth and metastasis. Animal/Disease Models: High-fat diet (HFD)-induced obese male C57BL/6 mice [2] Doses: 5 mg/kg; 12-week Route of Administration: subcutaneous injection; one time/day; 12-week Experimental Results: fibrosis progression was inhibited, high Fatty diet-induced non-alcoholic fatty liver disease is improved. For in vivo animal studies, the efficacy of PTUPB is typically assessed in mouse models of inflammation, cancer, and metabolic disease. In a tumor model, C57BL/6 mice are injected subcutaneously with LLC cells. When tumors reach a certain size, PTUPB is administered via subcutaneous injection using an Alzet mini-osmotic pump at a dose of 30 mg/kg once daily for 4 weeks. Tumor growth is monitored, and final tumor weights are recorded. In a model of NAFLD, male C57BL/6 mice are fed a high-fat diet (HFD) to induce obesity and NAFLD. PTUPB is administered via subcutaneous injection at a dose of 5 mg/kg once daily for 12 weeks. Body weight, liver weight, and hepatic triglyceride and cholesterol content are measured. The expression of genes related to lipogenesis and inflammation is analyzed by qRT-PCR. Inflammatory and oxidative stress markers are measured in serum and tissues. These studies provide critical data on the compound's in vivo efficacy and mechanism of action. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties for PTUPB are not extensively reported in the available literature. The compound is a small molecule with a molecular weight of approximately 400-500 (specific molecular weight not provided in the text). It is likely to be lipophilic, given its ability to inhibit sEH and COX-2, which are membrane-associated enzymes. The compound's route of administration in animal studies is subcutaneous injection, indicating that it may have limited oral bioavailability or that subcutaneous administration was chosen for sustained release. After subcutaneous injection at 5 mg/kg, PTUPB reaches peak plasma concentrations and improves NAFLD. However, specific pharmacokinetic parameters such as half-life, volume of distribution, and clearance have not been reported. The compound's metabolism is likely to involve hepatic cytochrome P450 enzymes. The compound's elimination route is unknown. Further studies are needed to fully characterize the pharmacokinetic profile of this compound.
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| Toxicity/Toxicokinetics |
Toxicological data for PTUPB indicates that it is well-tolerated in vivo at the doses tested. In a mouse tumor model, PTUPB (30 mg/kg; subcutaneous injection; 4 weeks) showed no overt effects, such as weight loss. No other specific toxicity studies, such as acute or chronic toxicity, genotoxicity, or cardiotoxicity, have been detailed in the public domain. The compound's selectivity for COX-2 over COX-1 (IC₅₀ >100 μM) suggests that it may have a favorable gastrointestinal safety profile compared to non-selective COX inhibitors. However, as with all research chemicals, standard safety precautions should be observed when handling this compound. The compound is not approved for clinical use and should only be used in preclinical research settings.
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| References |
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| Additional Infomation |
PTUPB is a research tool for studying the roles of sEH and COX-2 in inflammation, pain, and cancer. Its mechanism of action involves dual inhibition of sEH and COX-2. It inhibits sEH with an IC₅₀ of 0.9 nM and COX-2 with an IC₅₀ of 1.26 μM. It is not approved for clinical use.
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| Molecular Formula |
C26H24F3N5O3S
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|---|---|
| Molecular Weight |
543.560674667358
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| Exact Mass |
543.155
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| CAS # |
1287761-01-6
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| PubChem CID |
52951990
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.626
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| LogP |
4.91
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
862
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
CSEPEVFNTFMBAE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H24F3N5O3S/c27-26(28,29)19-8-10-20(11-9-19)32-25(35)31-16-4-7-21-17-24(18-5-2-1-3-6-18)34(33-21)22-12-14-23(15-13-22)38(30,36)37/h1-3,5-6,8-15,17H,4,7,16H2,(H2,30,36,37)(H2,31,32,35)
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| Chemical Name |
1-[3-[5-phenyl-1-(4-sulfamoylphenyl)pyrazol-3-yl]propyl]-3-[4-(trifluoromethyl)phenyl]urea
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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 : ~100 mg/mL (~183.97 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.83 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 (3.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8397 mL | 9.1986 mL | 18.3972 mL | |
| 5 mM | 0.3679 mL | 1.8397 mL | 3.6794 mL | |
| 10 mM | 0.1840 mL | 0.9199 mL | 1.8397 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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