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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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Ertiprotafib (PTP-112; PTP112) is a novel and potent Protein Tyrosine Phosphatase 1B Inhibitor (PTP1B inhibitor) with the ability to normalize the plasma glucose and insulin levels in diabetic animal models. It inhibits PTP1B and IkB kinaseβ (IKK-β), with IC50 values of 1.6 μM and 400 nM for PTP1B and IKK-β, respectively. It also acts as a dual PPARα and PPARβ agonist, with an EC50 value of ~1 μM for PPARα/PPARβ. Phase II clinical trials for the treatment of non-insulin dependent diabetes are currently being conducted with ertiprotafib. Through a variety of mechanisms, ertiprotafib enhances glycemic control and reduces lipids. With an IC(50) of 400 nM, ertiprotafib is a powerful inhibitor of IkappaB kinase beta (IKK-beta).
| Targets |
PTP1B (IC50 = 1.6 μM); IKK-β (IC50 = 400 nM); PPARα (EC50 ~1 μM); PPARβ (EC50 ~1 μM)
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|---|---|
| ln Vitro |
Ertiprotafib is a potent inhibitor of IKK-β, with an IC50 value of 400±40 nM, which is much lower than that required for the half-maximal inhibition of the p-nitrophenyl phosphatase activity of PTP1B. Depending on the assay parameters, the reported IC50 value of ertiprotafib for PTP1B ranges from 1.6 to 29 μM [2]. With EC50 values for transactivation of 1 μM, ertiprotafib is at least a dual PPARα and PPARβ agonist. Such behaviors easily account for the observations made when using suprapharmacologic doses of these[1].
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| ln Vivo |
Both Ertiprotafib and compound 3 seem to significantly improve glucose metabolism in rats, as was observed with treatment of ob/ob mice. When compared to rats given a vehicle treatment, these substances lower insulin and fasting blood glucose levels at a dose of 25 mg/kg/day. Additionally, after an oral challenge, the disposal of glucose is increased by compound 3 and ertiprotafib. A noteworthy finding is that treated animals have lower lipid levels. In rats treated with 25 mg/kg/day of either compound, triglyceride and free fatty acid levels are significantly decreased. To sum up, both ertiprotafib and compound 3 appear to be potent agents in increasing glucose utilization in fa/fa rats while also lowering lipid levels in these animals. It may surprise you to learn that a pure PTP1b inhibitor causes decreased lipid levels. As was already mentioned, it is more significant that rats given suprapharmacologic doses of ertiprotafib exhibit PPAR family activation[2].
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| Animal Protocol |
Mice, Rats: Male We use Zucker fa/fa rats and Ob/ob mice. They are fed Purina Mills' Rodent Diet 5001 (for mice and rats) and kept on a 12-hour/12-hour light/dark cycle. In an aqueous suspension of 2% Tween 80 and 0.5% methylcellulose, compounds are dosed orally by gavage. Glucose readings are taken from whole blood (5 μL) using the Ascensia Elite XL glucometer and glucose strips, which are loaded into the meter and then touched to a tiny drop of blood on each tail. By using an enzyme-linked immunosorbent assay, insulin levels can be measured[2].
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| References | |
| Additional Infomation |
Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test.
Ertiprotafib is an inhibitor of the protein tyrosine phosphatase 1B (PTP1B) and dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist with hypoglycemic and anti-lipidemic activity. Ertiprotafib inhibits PTP1B preventing the dephosphorylation of the insulin receptor, which improves insulin sensitivity and decreases blood glucose levels. In addition, this agent is able to stimulate both PPAR alpha and gamma thereby further improving glucose homeostasis and reducing triglyceride (TG) and free fatty acid levels. Ertiprotafib was also shown to be a potent inhibitor of IkappaB kinase beta (IKKbeta), which cotributes to its anti-inflammatory properties. Drug Indication Investigated for use/treatment in diabetes mellitus type 2. Mechanism of Action The complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPARalpha/PPARgamma agonism. |
| Molecular Formula |
C31H27BRO3S
|
|---|---|
| Molecular Weight |
559.52
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| Exact Mass |
558.086
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| Elemental Analysis |
C, 66.55; H, 4.86; Br, 14.28; O, 8.58; S, 5.73
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| CAS # |
251303-04-5
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| Related CAS # |
251303-04-5
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| PubChem CID |
157049
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| Appearance |
Light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
690.7±55.0 °C at 760 mmHg
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| Flash Point |
371.5±31.5 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.682
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| LogP |
10.9
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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 |
6
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| Heavy Atom Count |
36
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| Complexity |
744
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| Defined Atom Stereocenter Count |
1
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| SMILES |
BrC1C2=C([H])C([H])=C([H])C([H])=C2C(C2C([H])=C(C([H])([H])[H])C(=C(C([H])([H])[H])C=2[H])O[C@@]([H])(C(=O)O[H])C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])=C2C(C([H])([H])[H])=C(C([H])([H])[H])SC2=1
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| InChi Key |
FONCZICQWCUXEB-RUZDIDTESA-N
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| InChi Code |
InChI=1S/C31H27BrO3S/c1-17-14-22(15-18(2)29(17)35-25(31(33)34)16-21-10-6-5-7-11-21)27-23-12-8-9-13-24(23)28(32)30-26(27)19(3)20(4)36-30/h5-15,25H,16H2,1-4H3,(H,33,34)/t25-/m1/s1
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| Chemical Name |
(2R)-2-[4-(9-bromo-2,3-dimethylbenzo[f][1]benzothiol-4-yl)-2,6-dimethylphenoxy]-3-phenylpropanoic acid
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| Synonyms |
Ertiprotafib; PTP-112; PTP 112; PTP112
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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 (~178.7 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.47 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7872 mL | 8.9362 mL | 17.8725 mL | |
| 5 mM | 0.3574 mL | 1.7872 mL | 3.5745 mL | |
| 10 mM | 0.1787 mL | 0.8936 mL | 1.7872 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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