| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| 50mg |
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| Other Sizes |
| Targets |
CYP4A11 140 nM (IC50) CYP4F2 40 nM (IC50)
Cytochrome P450 isoforms CYP4A11 and CYP4F2. TP0472993 is a potent dual inhibitor of these enzymes, which are responsible for the synthesis of 20-HETE from arachidonic acid. By inhibiting CYP4A11 and CYP4F2, the compound reduces the production of 20-HETE, a vasoactive and pro-inflammatory eicosanoid involved in the pathogenesis of renal fibrosis and other diseases. It is selective for CYP4A11 and CYP4F2 over a panel of eight additional CYPs at 10 µM. |
|---|---|
| ln Vitro |
With an IC50 of 29 nM, CYP4A11/CYP4F2-IN-2 (compound 11c) suppresses the synthesis of 20-Hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid in human renal microsomes[1].
TP0472993 inhibits CYP4A11 and CYP4F2 with IC50 values of 140 nM and 40 nM, respectively. It inhibits 20-HETE production in rat renal microsomes with an IC50 of 347 nM. The compound suppresses 20-HETE synthesis from arachidonic acid in human renal microsomes. By reducing 20-HETE levels, it decreases ERK1/2 and STAT3 signaling pathway activity. |
| ln Vivo |
CYP4A11/CYP4F2-IN-2 (compound 11c) suppresses the synthesis of 20-HETE in the rats' kidneys in a dose-dependent manner (0.03-1 mg/kg; single po)[1]. Mice treated with 0.5 mg/kg of CYP4A11/CYP4F2-IN-2 show modest Vdss (763 mL/kg), short T1/2 (0.424 h), and low CL (1430 mL/h/kg)[1]. The study reports that in SD rats, CYP4A11/CYP4F2-IN-2 (1 mg/kg; iv) displays low CL (226 mL/h/kg), moderate Vdss (839 mL/kg), and T1/2 (3.01 h). In SD rats, CYP4A11/CYP4F2-IN-2 (1 mg/kg; po) shows a high bioavailability (97.7%), T1/2 (3.03 h), and Cmax (623 ng/mL[1].
In vivo, TP0472993 (0.03-1 mg/kg) inhibits 20-HETE production in rats. It reduces renal fibrosis and lowers IL-1β and TNF-α levels in a mouse model of folic acid-induced nephropathy. The compound's oral activity and ability to reduce renal fibrosis and inflammation make it a promising candidate for studying chronic kidney disease. Its effects on the ERK1/2 and STAT3 pathways contribute to its anti-fibrotic activity. |
| Enzyme Assay |
In vitro enzyme activity assays for TP0472993 typically involve measuring its ability to inhibit CYP4A11 and CYP4F2 enzymatic activity. Recombinant human CYP4A11 and CYP4F2 enzymes are incubated with their substrate (arachidonic acid) in the presence of increasing concentrations of the compound. The production of 20-HETE is measured by LC-MS/MS or other analytical methods, and the IC50 values are determined from dose-response curves.
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| Cell Assay |
In vitro cellular assays for TP0472993 involve treating renal cells or other relevant cell types with the compound and measuring its effects on 20-HETE production and downstream signaling pathways. Cells are stimulated with appropriate agonists, and 20-HETE levels are measured by LC-MS/MS. The phosphorylation of ERK1/2 and STAT3 is assessed by Western blot to confirm inhibition of these pathways.
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| Animal Protocol |
In vivo efficacy of TP0472993 is evaluated in animal models of renal fibrosis, such as the folic acid-induced nephropathy mouse model. The compound is administered orally at doses ranging from 0.03 to 1 mg/kg. Efficacy endpoints include reduction of 20-HETE production, renal fibrosis, and inflammatory cytokine levels (IL-1β, TNF-α). Kidney histology and function are also assessed.
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| ADME/Pharmacokinetics |
TP0472993 has a molecular weight of 300.36 g/mol and a molecular formula of C16H20N4O2. It is orally active and soluble in DMSO (25 mg/mL). The compound should be stored as a powder at -20°C and protected from light. Pharmacokinetic properties are consistent with oral bioavailability, though detailed PK parameters are not extensively reported in the available literature.
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| Toxicity/Toxicokinetics |
No specific toxicity data is detailed for TP0472993 in the available literature. As a research compound, its safety profile would be an important consideration for in vivo applications. Potential toxicities could be related to its effects on 20-HETE production and CYP enzyme inhibition in various tissues. Standard preclinical safety studies would be required to evaluate its safety for potential therapeutic applications.
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| References | |
| Additional Infomation |
TP0472993 (CYP4A11/CYP4F2-IN-2) is a novel, orally active, and selective inhibitor of 20-HETE synthesis. It functions as a potent dual inhibitor of CYP4A11 and CYP4F2. By reducing 20-HETE production, it decreases ERK1/2 and STAT3 signaling, ultimately inhibiting renal fibrosis progression. TP0472993 has potential for studying chronic kidney disease (CKD). It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C16H20N4O2
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|---|---|
| Molecular Weight |
300.355603218079
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| Exact Mass |
300.158
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| CAS # |
2126874-77-7
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| PubChem CID |
130360508
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| Appearance |
White to off-white solid powder
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| LogP |
1.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
371
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(=O)(N1CCC(COC2=CC=C(C3C=CNN=3)N=C2)CC1)C
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| InChi Key |
GNQGSUOEYQIORN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H20N4O2/c1-12(21)20-8-5-13(6-9-20)11-22-14-2-3-15(17-10-14)16-4-7-18-19-16/h2-4,7,10,13H,5-6,8-9,11H2,1H3,(H,18,19)
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| Chemical Name |
1-[4-[[6-(1H-pyrazol-5-yl)pyridin-3-yl]oxymethyl]piperidin-1-yl]ethanone
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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: 25 mg/mL (83.23 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.32 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.32 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 25.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3293 mL | 16.6467 mL | 33.2934 mL | |
| 5 mM | 0.6659 mL | 3.3293 mL | 6.6587 mL | |
| 10 mM | 0.3329 mL | 1.6647 mL | 3.3293 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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