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Application of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate in preparing an LSD1 (lysine-specific demethylase 1) inhibitor medicament

A technology of inhibitors and drugs, applied in the field of pharmacy, can solve the problems of poor selectivity of MAOs, large toxic and side effects, low selectivity of homologous protein MAOs, etc., and achieve good inhibitory effect

Inactive Publication Date: 2014-07-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The most studied is the phenylcyprotamine-based LSD1 inhibitor, which covalently binds to FAD in its molecular structure to inhibit the biological function of LSD1. The selectivity of MAOs is poor, so the toxic and side effects are relatively large
In addition, the reported LSD1 inhibitors are generally not very selective for the homologous protein MAOs.

Method used

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  • Application of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate in preparing an LSD1 (lysine-specific demethylase 1) inhibitor medicament
  • Application of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate in preparing an LSD1 (lysine-specific demethylase 1) inhibitor medicament
  • Application of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate in preparing an LSD1 (lysine-specific demethylase 1) inhibitor medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The LSD1 in vitro screening of embodiment 1 formula I compound

[0023] 1. Reagents and raw materials

[0024] LSD1: (Enzo cat#BML-SE544, N-terminal truncated LSD1 is derived from human cDNA expressed in Escherichia coli, the sequence is the same as GenBank NM015013 (amino acid 151-852), relative molecular weight: 78kDa)

[0025] Reaction substrate: 10 μM 21 peptide of dimethylated H3K4 (Histone H3peptide (1-21) K4me2, 10 μM)

[0026] Basic reaction buffer: 50 mM Tris-HCl, pH 7.5 and 1% DMSO

[0027] Reaction conditions: 100 nM LSD1 and 10 μM dimethylated H3K4 21 peptide

[0028] 2. Operation steps

[0029] 2.1 Demethylation step

[0030] (1) Add 2 times the amount of LSD1 to each reaction well

[0031] (2) Apply Acoustic technology (Echo550; nanoliter range) to dissolve the sample to be tested with 100% DMSO and add to the enzyme, reduce the speed and pre-incubate for 15 minutes.

[0032] (3) Add 2 times the amount of substrate mixture (except for control wells w...

Embodiment 2

[0041] Embodiment 2 formula I compound to the in vitro screening of MAO-A and MAO-B

[0042] 1. Reagents and raw materials

[0043] MAO-A: Sigma cat#M7316 (human recombinant, expressed in baculovirus-infected BTI insect cells, 84U / mg).

[0044] MAO-B: Sigma cat#M7441 (human recombinant, expressed in baculovirus-infected BTI insect cells, 71U / mg.)

[0045] Substrate: 10 μM Tyramine

[0046] Basic reaction buffer: 50 mM Tris-HCl, pH 7.5 and 1% DMSO

[0047] Reaction conditions: MAO-A (0.5U / ml), MAO-B (1U / ml) and tyramine (10μM)

[0048] 2. Operation steps

[0049] 2.1 Demethylation step

[0050] (1) Add 2 times the amount of LSD1 to each reaction well

[0051] (2) Using Acoustic technology (Echo550; nanoliter range), the sample to be tested was dissolved in 100% DMSO and added to the enzyme, the speed was reduced and pre-incubated for 15 minutes.

[0052] (3) Add 2 times the amount of substrate mixture (except for control wells without substrate) to initiate the reaction....

Embodiment 3

[0064] The tablet preparation of embodiment 3 formula I compound

[0065] Using wet granulation and tabletting method, the compound of formula I is mixed with various excipients such as hydroxypropylmethylcellulose E5, microcrystalline cellulose MCC102, 8% povidone K30 and magnesium stearate according to the following ratio, pulverized and sieved , Granulating, drying, and tableting to make corresponding tablets.

[0066]

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Abstract

The invention belongs to the field of medicine, and in particular relates to a medical application of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate in a selective histone lysine-specific demethylase 1 (LSD1) inhibitor, especially the application in anti-tumor medicaments. Pharmacodynamic tests indicate that the 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl) amino)-4-oxobutanoate has a remarkable LSD1 inhibiting effect, and has selectivity to homologous proteins MAO-A (monoamine oxidase-A) and MAO-B.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)- Medicinal use of 4-oxobutyrate as a selectively acting histone lysine-specific demethylase 1 (LSD1) inhibitor. The present invention also relates to 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxo The medical application of the pharmaceutical preparation or pharmaceutical composition of the butyrate, especially the application in the preparation of antitumor drugs. Background technique [0002] In 2004, Shi Yang's research group at Harvard Medical School discovered the first histone lysine-specific demethylase 1 (Lysine Specific Demethylase1, LSD1), and confirmed for the first time that histone methylation is a dynamic equilibrium process (Cell , 2004, 119:941-953), this revolutionary discovery provides a new research idea for the mechanism of histone modification and its corresponding d...

Claims

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Application Information

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IPC IPC(8): A61K31/222A61P35/00A61P31/12A61P25/28A61P35/02
Inventor 查晓明康迪周忱徐云根
Owner CHINA PHARM UNIV
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