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2-([1,1′-biphenyl]-4-yl)2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxobutyrate Application of lsd1 inhibitor drugs

An inhibitor, lysine technology, 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 the effect of good inhibitory activity

Inactive Publication Date: 2016-02-03
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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  • 2-([1,1′-biphenyl]-4-yl)2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxobutyrate Application of lsd1 inhibitor drugs
  • 2-([1,1′-biphenyl]-4-yl)2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxobutyrate Application of lsd1 inhibitor drugs
  • 2-([1,1′-biphenyl]-4-yl)2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxobutyrate Application of lsd1 inhibitor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 In vitro screening of LSD1 compound of formula I

[0023] 1. Reagents and raw materials

[0024] LSD1: (Enzocat#BML-SE544, the N-terminal truncated LSD1 is derived from human cDNA expressed in E. coli, the sequence is the same as the gene bank NM015013 (amino acids 151-152), relative molecular weight: 78kDa)

[0025] Reaction substrate: 10μM dimethylated H3K4 21 peptide (HistoneH3peptide(1-21)K4me2, 10μM)

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

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

[0028] 2. Operation steps

[0029] 2.1 Demethylation steps

[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 it to the enzyme, slow down and pre-incubate for 15 minutes.

[0032] (3) Add 2 times the amount of the substrate mixture (except for the control well without substrate) to initiat...

Embodiment 2

[0041] Example 2 In vitro screening of the compound of formula I on MAO-A and MAO-B

[0042] 1. Reagents and raw materials

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

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

[0045] Substrate: 10μM Tyramine

[0046] Alkaline reaction buffer: 50mM 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 steps

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

[0051] (2) Apply Acoustic technology (Echo550; nanoliter range) to dissolve the sample to be tested with 100% DMSO and add it to the enzyme, slow down and pre-incubate for 15 minutes.

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

Embodiment 3

[0064] Example 3 Tablet preparation of compound of formula I

[0065] Using wet granulation and tableting method, the compound of formula I and various excipients such as hydroxypropyl methylcellulose E5, microcrystalline cellulose MCC102, 8% povidone K30 and magnesium stearate are mixed in the following proportions, crushed and sieved , Granulation, drying and compression 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 present invention belongs to the field of pharmacy, and specifically relates to 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)- 4-oxobutyrate is used as a selective inhibitor of histone lysine-specific demethylase 1 (LSD1) in medicine. The present invention also relates to 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl 4-((3-chloro-4-methylphenyl)amino)-4-oxo The medical use of butyrate's pharmaceutical preparations or pharmaceutical compositions, especially the application in the preparation of anti-tumor 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 Demethylase 1, LSD1), confirming 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 on the mechanism of histone modification and its corresponding drug...

Claims

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Application Information

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