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TTPU is a novel and potent soluble epoxide hydrolase (sEH) inhibitor with anti-inflammatory effects. It has an IC50 of 37 and 3.7 nM for monkey and human sEH, respectively.
| Targets |
Soluble epoxide hydrolase (sEH) inhibitor. The IC₅₀ for cynomolgus monkey hepatic cytosolic sEH is 37 ± 4 nM (using [³H]-t-DPPO assay). The IC₅₀ for recombinant human sEH is 3.7 ± 0.4 nM (using fluorescent assay) or 48 nM (using [³H]-t-DPPO assay).[1]
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| ln Vitro |
Soluble epoxide rapid enzyme conjugation (sEHI) possesses anti-inflammatory, anti-atherosclerotic, anti-hypertensive and analgesic properties [1]. In the Caco-2 cell permeability assay, TPPU went through the cell monolayer, showing that it has good destruction permeability [2].
TPPU demonstrated potent inhibitory activity against soluble epoxide hydrolase (sEH) isolated from cynomolgus monkey liver cytosol.[1] Among the piperidine-containing urea inhibitors tested, TPPU was the most potent against the cynomolgus monkey sEH.[1] |
| ln Vivo |
The biology of soluble epoxide resting enzymes and the function of epoxide-containing rosettes in regulatory regulation can both be studied with TPPU. At a dosage of 0.3 mg/kg, TPPU exhibited high rose concentration and drug-like characteristics. Cmax for TPPU rises from 0.3 to 3 mg/kg with dosage [1]. The blood concentration of TPPU showed a dose-dependent rise after treatment following incubation in water (0.2, 1 and 5 mg TPPU/L with 0.2% PEG400) and reached an almost steady condition after 8 days [2]. Animal models of depression show antidepressant benefits from sEH reverse TPPU. sEH preventative sEH inhibition or sEH-KO results in recovery from the stress of repeated social defeat in the brains of chronic intermittent and depressed patients and is linked to enhanced BDNF-TrkB signaling in the KO prefrontal layer and hippocampus [3].
In cynomolgus monkeys, oral administration of TPPU at doses of 0.3, 1, and 3 mg·kg⁻¹ resulted in a dose-dependent increase in the plasma ratio of linoleate epoxides (EpOMEs) to diols (DHOMEs), indicating target engagement and inhibition of sEH activity in vivo. The EpOME:DHOME ratio increased at 4 and 48 hours post-dosing for the 0.3 and 1 mg·kg⁻¹ doses. The increase was more pronounced at 48 hours.[1] The effect on arachidonate epoxide (EET) to diol (DHET) ratios was less clear, although the 8,9-EET:DHET regioisomer ratio showed a pattern similar to the linoleate metabolites.[1] Administration of TPPU also modulated plasma levels of other oxylipins, including decreasing pro-inflammatory COX-2 metabolites (PGF₂α, PGE₂), certain CYP450 metabolites (TriHETrE, 20-HETE), and the LOX metabolite 20-COOH-LTB₄.[1] |
| Enzyme Assay |
The inhibitory potency (IC₅₀) of TPPU against cynomolgus monkey sEH was determined using a radioactive partition assay with [³H]-trans-diphenyl propene oxide ([³H]-t-DPPO) as the substrate. Monkey liver cytosol fraction was diluted and incubated with the substrate (50 μM final concentration) and various concentrations of the inhibitor (1-50000 nM) for 10 minutes at 30°C. The reaction was stopped by extraction, and the amount of radioactive diol formed in the aqueous phase was measured to determine enzyme activity. IC₅₀ values were calculated from the dose-response curve of log inhibitor concentration versus percent inhibition.[1]
For comparison, the IC₅₀ against recombinant human sEH was determined using a fluorescent substrate assay, and in some cases also verified with the [³H]-t-DPPO assay.[1] |
| Animal Protocol |
TPPU was administered orally to female cynomolgus monkeys (Macaca fascicularis) to assess its pharmacokinetics and pharmacodynamics.[1]
For initial cassette dosing (along with other compounds), TPPU was dissolved in a formulation of 10% PEG-400 in safflower oil to create a true solution. It was administered via gastric intubation at a dose of 0.3 mg·kg⁻¹ to fasted, sedated animals. Blood samples (10 μL) were collected from the tail vein at various time points post-dosing.[1] For dose-escalation studies, TPPU was prepared at doses of 0.3, 1, and 3 mg·kg⁻¹ and administered orally to four animals with 48-hour dosing intervals. Blood was collected at multiple time points after each dose.[1] |
| ADME/Pharmacokinetics |
Following a single oral dose of 0.3 mg·kg⁻¹ in cynomolgus monkeys, the maximum plasma concentration (Cₘₐₓ) of the TPPU was 760 ± 80 nM, and the time to peak concentration (Tₘₐₓ) was 4 ± 3 hours. The area under the plasma concentration-time curve (AUC₀₋₇₂) from 0 to 72 hours was 28 ± 23 h·μM. The plasma concentration remained higher than its IC₅₀ value for cynomolgus monkey enzymes for at least 48 hours after administration. [1]
Dose escalation studies (0.3, 1, 3 mg·kg⁻¹) showed that Cₘₐₓ and AUC increased with increasing dose, but not in a completely linear manner. At doses of 0.3, 1, and 3 mg·kg⁻¹, the Cₘₐₓ values were 0.7 ± 0.6, 4.5 ± 1.5, and 16.5 ± 4.6 μM, respectively, and the AUC₀₋₄₈ values were 23 ± 17, 120 ± 40, and 460 ± 260 h·μM, respectively. Tₘₐₓ increased with increasing dose. [1] TPPU exhibited drug-like physicochemical properties, including higher water solubility, lower melting point, moderate log P value, and lower plasma protein binding, indicating more free drug available to enter tissues compared to 4-(cyclohexyloxy)benzoic acid urea sEH inhibitors. [1] |
| References |
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| Additional Infomation |
TPPU is a piperidinylurea soluble epoxide hydrolase inhibitor (sEHI). Due to its high in vitro activity, good pharmacokinetic characteristics (high AUC, long effective half-life), drug-like properties, and significant target binding in vivo (which can be measured by changes in the plasma oxylipin ratio), it is considered a promising candidate drug for long-term research in non-human primates. [1]
The study concluded that TPPU is suitable for studying the biology of sEH and the role of epoxide-containing lipids in the regulation of inflammatory diseases in non-human primates. [1] |
| Molecular Formula |
C16H20N3O3F3
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|---|---|
| Molecular Weight |
359.3435
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| Exact Mass |
359.145
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| CAS # |
1222780-33-7
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| PubChem CID |
44142782
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
448.9±45.0 °C at 760 mmHg
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| Flash Point |
225.3±28.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.532
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| LogP |
2.32
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
457
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
AAJMQTLFRTZCJK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H20F3N3O3/c1-2-14(23)22-9-7-12(8-10-22)21-15(24)20-11-3-5-13(6-4-11)25-16(17,18)19/h3-6,12H,2,7-10H2,1H3,(H2,20,21,24)
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| Chemical Name |
1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)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 : ~83.33 mg/mL (~231.90 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.79 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 (5.79 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 (5.79 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 | 2.7829 mL | 13.9144 mL | 27.8288 mL | |
| 5 mM | 0.5566 mL | 2.7829 mL | 5.5658 mL | |
| 10 mM | 0.2783 mL | 1.3914 mL | 2.7829 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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