Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor

A technology of compound and application, applied in the field of preparation of selective FTO inhibitors, capable of solving problems such as lack of FTO inhibitors

Active Publication Date: 2014-10-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In summary, there is still a lack of FTO inhibitors that specifically target FTO in this area.

Method used

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  • Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor
  • Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor
  • Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

experiment Embodiment 1

[0131] Experimental example 1: Fluorescence polarization test detects the selective inhibition of FTO and ALKBH5 by 2-(substituted anilino)benzoic acid and its esters

[0132] The substrate for the fluorescence polarization experiment is fluorescently labeled ssDNA with the sequence 5'-ATTGTCA(m 6 A) CAGCAGA-FAM-3'. The reaction solution contains 50mM boric acid buffer (pH7.5), 20nM ssDNA, 3μM FTO or 3μM ALKBH5, and the final volume is 100μL. After incubation at room temperature for 30min, the fluorescence polarization value is read by a microplate reader, and the detection wavelength is the excitation light at 480nm and the emission Light 520nm. Inhibition curves and parameters via GraphPad Prism5.0 TM The nonlinear fitting is carried out. The fluorescence polarization value represents the binding force parameter between the protein and the substrate ssDNA. From the attached figure 1 In Figure A, it can be seen that compound FTO-A-11 can reduce the polarization value in a ...

experiment Embodiment 2

[0133] Experimental Example 2: Differential Scanning Fluorescence Experiment Detects the Selective Inhibition of 2-(Substituted Anilino)benzoic Acid and Its Esters to FTO and ALKBH5

[0134] The reaction system was 5×SYPRO Orange dye, FTO-A-11 concentration gradient compound, 2 μM FTO or ALKBH5, and 1.5% DMSO was used as a control. The experiment was tested by an ABI7500 quantitative PCR instrument, and the temperature of the reaction solution rose from 25°C to 95°C with a rate of 1% slope. The excitation wavelength and emission wavelength were 492nm and 610nm, respectively. All experiments were repeated three times. Melting curve by Graphpad Prism5.0 TM to fit. From attached figure 2 In Figure B, it can be seen that compound FTO-A-11 has inhibitory activity on FTO, and it can be seen from Figure A that compound FTO-A-11 has no inhibitory activity on ALKBH5, indicating that FTO-A-11 can selectively inhibit FTO activity. However, it has no effect on ALKBH5 activity.

experiment Embodiment 3

[0135] Experimental Example 3: Non-denaturing polyacrylamide gel electrophoresis test for selective inhibition of FTO and ALKBH5 by 2-(substituted anilino)benzoic acid and its esters

[0136] The reaction substrate single-stranded DNA (ssDNA) sequence is 5'-TAGACATTGCCATTCTCGATAGG(m 6 A) TCCGGTCAAACCTAGACGAATTCCA-3', which contains a DpnII restriction site. The reaction system was 50 mM tris(hydroxymethyl)aminomethane-hydrochloric acid buffer (pH7.5), 1 μM ssDNA, 300 μM α-ketoglutarate (2OG), 280 μM ferrous ammonium sulfate ((NH 4 ) 2 Fe(SO 4 ) 2 ), 2 mM L-ascorbic acid, concentration gradient compound FTO-A-11, 1 μM FTO, ALKBH2, ALKBH3 or ALKBH5. After the reaction solution was incubated at room temperature for 2 h, it was quenched by heating. The ssDNA was annealed with its complementary strand to form a double-stranded DNA, which was digested with DpnII, then detected by 15% non-denaturing polyacrylamide gel electrophoresis, and the intensity of the band was detected a...

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Abstract

The invention provides use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of an FTO (Fat Mass and Obesity-Associated Protein) inhibitor. The invention particularly discloses the use of 2-(substituted phenylamino)-benzoic acid and the ester compound and a pharmaceutically acceptable salt thereof which are shown in the formula I in preparation of the FTO inhibitor or a pharmaceutical composition for treating FTO-related diseases.

Description

technical field [0001] The present invention relates to the field of medicines, and specifically, the present invention provides a use of a compound having a structure of formula (I) for preparing a selective FTO inhibitor. Background technique [0002] As we all know, the intake of high-calorie food and lack of exercise lead to more and more people becoming obese. Currently, there are about 1.7 billion overweight people in the world. Obesity not only brings inconvenience to people's daily life, but also many diseases are directly related to obesity, such as metabolic syndrome (metabolic syndrome, MS) and type 2 diabetes (Type 2 diabetes, T2D). Recent studies have also found that obesity also increases the risk of cardiovascular disease (CVD), high blood pressure, Alzheimer's disease and cancer. In 2000, there were about 177 million people with type 2 diabetes. At that time, the World Health Organization estimated that there would be about 377 million people with type 2 dia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/196A61K31/4409A61K31/245C07C229/58C07C229/60C07C255/58C07C229/62C07C229/64C07D213/36A61P3/00A61P3/10A61P9/00A61P9/12A61P9/10A61P35/00
Inventor 杨财广罗成黄悦巩守哲李家飞蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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