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PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, and synthesis and application thereof

An inhibitor and chemical synthesis technology, applied in the field of biomedicine, can solve the problems of few, low druggability, poor selection specificity, etc.

Inactive Publication Date: 2011-06-22
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are not many studies on PTP1B inhibitors in the world, mainly in the following categories: (1) Peptides: peptide substrates containing phosphorylated tyrosine residues (pTyr) have a higher affinity with PTP1B, But its chemical and biological stability are poor; (2), naphthoquinones Naphthnoquinone: inhibit the activity of enzyme by modifying the active site of PTPase; (3), thiazolidinediones Azolidinediones: increase the insulin sensitivity of target organ Improve blood sugar control, mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b]naphthol[2,3-d]furans and thiophenes: benzbromarone (PTP1B inhibitor, IC 50 =26μM) as the lead compound designed and synthesized as a series of Benzo[b]naphthol[2,3-d]furans and thiophenes compounds, which showed good hypoglycemic activity in mice, but it still needs to be used as a drug for treating diabetes. Overcoming many obstacles, such as high electronegativity, poor cell membrane permeability, and poor selective specificity, all of which make these inhibitors less druggable

Method used

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  • PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, and synthesis and application thereof
  • PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, and synthesis and application thereof
  • PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, and synthesis and application thereof

Examples

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Embodiment 1

[0032] Example 1 The chemical synthesis and structure of "(2'-bromo-4', 5'-dihydroxy-phenyl)-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane" identification

[0033] (1) Chemical synthesis and structure identification of Bis-(3,4-dimethoxy-phenyl)-methanone 3

[0034] Add 22.08g (120mmol) veratrol (compound 1), 16.92g (120mmol) veratrol (compound 2) and 100g polyphosphoric acid into a 250ml three-necked reaction flask according to the molar ratio of 1:1, and stir at 80°C for reaction 1h; cool to 60°C and add 250ml of ice water dropwise to the reactant within 30min, at this time, a large amount of water-insoluble pink solid precipitates out of the reactant; after removing water by filtration, dissolve the obtained solid in 100ml of dichloromethane , washed three times with an equal volume of 3% sodium hydroxide solution and distilled water successively; after drying the dichloromethane phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain a pink solid; w...

Embodiment 2

[0044] Example 2 Determination of protein tyrosine phospholipase 1B inhibitory activity

[0045] The test compound "(2'-bromo-4', 5'-dihydroxy-phenyl)-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane" was prepared in DMSO into different Concentration of the test solution, take 2μL of the test solution were added to the standard bioassay system (50mM Tris-HCl, PH 6.5, 2mM pNPP, 2% DMSO, 30nM hGST-PTP1B), negative control: DMSO, positive control : Sodium orthovanadate, the reaction temperature is 30°C, the light absorption at the wavelength of 405nm is dynamically measured for 3min, and the inhibition rate of compound PTP1B enzyme activity is calculated according to the following formula. Inhibition rate=(experimental group A value-negative control group A value) / (control group A value-negative control group A)×100%, the results are shown in Table 1.

[0046] Table 1 protein tyrosine phospholipase 1B inhibition rate (%)

[0047] Table 1 Inhibitory Ratio(%)of PTP1B

[0048] ...

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Abstract

The invention relates to a novel chemical complete synthesis method of a PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor and application of the PTP1B inhibitor in medicaments for treating Type 2 diabetes. The chemical structural formula of the PTP1B inhibitor is disclosed in the specification, wherein groups connected to the 2-site, 2'-site and 3-site carbons of the benzene ring are bromine atoms; the 4-site, 4'-site, 5-site and 5'-site carbons are connected to hydroxyl groups; and the English chemical name of the compound is (2'-bromo-4',5'-dihydroxy-phenyl)-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane. By inhibiting the activity of the protein tyrosine phosphatase 1B, the compound enhances the insulin receptor sensitivity, and has favorable therapeutic action on insulin resistance Type 2 diabetes.

Description

technical field [0001] The present invention relates to biomedicine, specifically a brominated compound "(2'-bromo-4',5'-dihydroxy-phenyl)-(2,3-dibromo-4,5-dihydroxy- Phenyl)-methane" and its chemical total synthesis method, pharmacological activity and pharmaceutical use. As an insulin sensitizer, the compound and its derivatives can be used for treating insulin-resistant type 2 diabetes. Background technique [0002] Diabetes Mellitus (DM) is a chronic endocrine and metabolic disease. According to the International Diabetes Federation (IDF) data in 2007, the number of adult diabetic patients in the world is about 246 million, of which type 2 diabetes (T2DM) patients account for 90% of the total diabetic patients above. By 2025, the number of people with diabetes worldwide is expected to reach 380 million. The drugs currently used to treat T2DM mainly include biguanides, sulfonylureas, α-glucosidase inhibitors, and thiazolidinediones, etc., because most of them are desig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C39/367C07C37/055A61K31/055A61P3/10A61P43/00
Inventor 李敬郭书举韩丽君史大永袁毅
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI