Application of N-aryl, benzyl tryptanthrin and derivatives thereof in preparation of hIDO2 inhibitors

A technology of use and preparation, applied in the field of medicinal chemistry

Active Publication Date: 2017-07-07
SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are relatively few studies on the biological characteristics, function and immune tolerance of IDO2. There is an urgent need in this field to develop highly effective and selective inhibitors of IDO2, so as to treat IDO2 alone or IDO1 and IDO2. Provide new drug targets and ideas for major human diseases

Method used

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  • Application of N-aryl, benzyl tryptanthrin and derivatives thereof in preparation of hIDO2 inhibitors
  • Application of N-aryl, benzyl tryptanthrin and derivatives thereof in preparation of hIDO2 inhibitors
  • Application of N-aryl, benzyl tryptanthrin and derivatives thereof in preparation of hIDO2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Preliminary Screening of IDO2 Inhibitors at Enzyme Level

[0093] In a 500 μL standard detection system, 50 mmol / L potassium phosphate buffer (pH 7.5), 200 μg / mL catalase, 40 mmol / L ascorbic acid, 20 μmol / L methylene blue, a suitable concentration of the substrate L-tryptophan and the final Mix the IDO2 inhibitor to be tested (including the compound of the present invention, L-1-MT and D-1-MT) with a concentration of 10 μM, put the mixed solution in a water bath at 37°C for 5 minutes, add IDO2 to the above mixed solution, and react at 37°C for 30 minutes After the end of the enzymatic reaction, 200 μL of 30% (w / v) trichloroacetic acid was added to stop the reaction, and then heated in a water bath at 65°C for 15 minutes to complete the reaction product from N-formylkynurenine to kynurenine transform. Centrifuge at 138,000×g for 10 minutes, draw 100 μL of the supernatant and mix well with an equal volume of 2‰ (w / v) acetic acid solution of p-dimethylaminobenzaldehyde, k...

Embodiment 2

[0096] Determination of inhibition type and Ki value of compounds of the present invention

[0097] In the 500 μL detection system described in Example 1, the substrate L-tryptophan of different concentrations (20, 30, 40 mM or 20, 25, 35 mM) were added, and at each substrate concentration, different concentrations Gradient inhibitors to be tested (including the compound of the present invention, L-1-MT and D-1-MT), no inhibitor was added to the control group, 10 μL IDO2 (about 1 μM) was added to the mixed solution in a water bath at 37°C for 5 minutes, and 37°C React for 30 minutes, add 200 μL of 30% (w / v) trichloroacetic acid to terminate the reaction after the enzymatic reaction, and then heat in a water bath at 65°C for 15 minutes to complete the reaction product from N-formylkynurenine to kynurenine acid conversion. Centrifuge at 138,000×g for 10 minutes, draw 100 μL of the supernatant and mix well with an equal volume of 2‰ (w / v) acetic acid solution of p-dimethylaminob...

Embodiment 3

[0103] The half effective inhibitory concentration IC of the compound of the present invention 50 Determination of value

[0104] The ICs of compounds of the present invention inhibiting IDO1 and IDO2 were measured in vitro and at the cellular level respectively 50 value.

[0105] In vitro level (enzyme level): In the 500 μ L detection system described in embodiment 1, add the substrate L-tryptophan of 30 mM and the inhibitor of different concentration gradient (comprising compound of the present invention, L-1-MT and D- 1-MT), the control group did not add inhibitors, and other treatments were the same as in Example 1. After the reaction, a microplate reader was used to detect the absorbance at 492nm. The inhibition rate was plotted against the concentration of the inhibitor, and the IC was calculated using the modified Cole's method 50 value.

[0106] Cell level: U87MG cell line (ATCC No.: HTB-14), cultured in DMEM high glucose containing 10% fetal bovine serum at 37°C, ...

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Abstract

The invention provides an indoleamine 2, 3-dioxygenase 2 inhibitor and application thereof, and particularly provides a formula-I compound or pharmaceutically-acceptable sodium thereof. The compound has excellent effects of inhibiting indoleamine 2, 3-dioxygenase 2 activity and resisting tumors. The invention further provides a drug composition containing the compound and application of the drug composition in resisting indoleamine 2, 3-dioxygenase.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more specifically to the compound of formula I and its application in inhibiting indoleamine 2,3-dioxygenase 2. Background technique [0002] Indoleamine 2,3-dioxygenase 1 (indoleamine2,3-dioxygenase1, IDO1) is the first rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway in mammals. Studies have shown that IDO1 is highly expressed in a variety of tumor tissues, which can inhibit the proliferation of lymphocytes by reducing the concentration of tryptophan in the tumor microenvironment, and play an important role in tumor immune escape. Therefore, it is currently believed that the high expression of IDO1 is It is one of the important factors leading to the body's immune tolerance to tumors. [0003] In 2007, Ball et al. discovered an enzyme that is very similar to IDO1 in terms of coding gene sequence, molecular structure and biological activity...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P35/00A61P31/18A61P25/28A61P25/24A61P27/12
CPCC07D487/04A61K31/519A61K31/5377Y02P20/55
Inventor 匡春香杨春
Owner SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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