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Hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug and preparation method and medical application thereof

A technology of hydrogen peroxide and inhibitors, applied in pharmaceutical formulations, antipyretics, anti-inflammatory agents, etc., can solve problems such as limiting the therapeutic use of chronic inflammatory diseases

Active Publication Date: 2020-02-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most currently available H 2 o 2 Responsive prodrugs are developed against cancer drugs, and few drugs have been shown to be effective in vivo
What's more, there is still no oral H 2 o 2 Responsive prodrugs, which limit their therapeutic use in chronic inflammatory diseases

Method used

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  • Hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug and preparation method and medical application thereof
  • Hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug and preparation method and medical application thereof
  • Hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Synthesis and structure confirmation of the target compound

[0034] 1. Preparation of intermediates

[0035] 1.1 Preparation of 14-methoxy-N-(naphthalene-1-yl)benzenesulfonamide (5)

[0036] 4-Nitronaphthalene-1-amine (4) (3 g, 15.9 mmol) was dissolved in THF solution, and a catalytic amount of palladium carbon was added to react for 5 h, and the catalyst was removed by filtration with diatomaceous earth. The crude naphthalene-1,4-diamine was used without further purification. 4-Methoxybenzenesulfonyl chloride (2.99g, 14.5mmol) and sodium carbonate (2.53g, 23.9mmol) were added to the filtrate, and the reaction solution was stirred in an ice bath under nitrogen protection for 2 hours. After the reaction was complete, sodium carbonate was filtered and the filtrate was collected. Recrystallization from acetonitrile gave a pink solid (3.12 g, 62% yield). R f =0.37(EA / PE2:1); m.p.169-171°C; 1 H-NMR (300MHz, DMSO-d 6 ):δ=9.39(s,1H; NH), 8.05–7.93(m,1H; Ar-H...

Embodiment 2

[0049] Embodiment 2: the pharmacokinetic characteristic of target compound

[0050] 1. Pharmacokinetic experiment

[0051] 1.1, HPLC determination of drug release rate

[0052] The target compound was dissolved in DMSO to a stock solution with a concentration of 10 mM and stored at -20°C. By adding the target compound (10 mM) to phosphate buffered saline (PBS) (10 mM, pH 7.4) to a final concentration of 50 μM, and then adding HO 2 o 2 , vortex to mix the solution. The solution was incubated at 37°C. Samples were taken at appropriate time intervals and analyzed directly after injection by HPLC, the peak area was recorded to calculate the percentage of the compound, and the experiment was repeated three times. The following Agilent 1260 HPLC and DAD detectors were used: Agilent C18 chromatographic column (4.6×150 mm, 3.5 μm); mobile phase: methanol 70%; flow rate: 0.5 mL / min. Draw a standard curve of the compound against the concentration.

[0053] 1.2. Determination of i...

Embodiment 3

[0072] Embodiment 3: Anti-inflammatory activity evaluation of target compound

[0073] 1. Anti-inflammatory activity experiment

[0074] 1.1. LPS-induced ROS generation (DCFH-DA method)

[0075] RAW264.7 cells at 37°C with 5% CO 2 Pretreatment with 0.3125, 0.625, 1.25, 2.5, 5, 10, 20 ng / mL of LPS in humidified air for 8 hours. A control group was cultured in the same medium without adding LPS. Afterwards, the cells were incubated in DCFH-DA (10 μM) at 37° C. for 30 minutes, and then the cells were washed 3 times, collected, and resuspended in PBS. Fluorescence was detected with a thermoscientific microplate reader.

[0076] 1.2. Detection of ARE-luciferase activity

[0077] HepG2-ARE-C8 cells were divided into 4×10 4 Cells / well density were seeded in 96-well plates and incubated overnight. Then different concentrations of test compounds were added to incubate the cells, DMSO was used as a negative control, and luciferase cell lysis reagent was used as a blank. After 12...

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Abstract

The invention discloses a hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug, and a preparation method and medical application thereof. The hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug pro2 has a chemical structure as shown in the specification. According to the invention, a thiazolidinone part responsive to H2O2 is used for modifying a key carboxyl pharmacophore in a Keap1-Nrf2 inhibitor, and thus, the novel ROS responsive antioxidant prodrug pro2 is synthesized. The H2O2 activated prodrug pro2 can simultaneously realize the effects of targeted activation of Nrf2 and enhancement of in-vivo treatment efficacy, is based on the concept therapy of ROS activation-ROS removal, is also a first H2O2 responsive prodrug example suitable for oral administration, has the characteristics of druggability and high targeting, and is thus expected to be used clinically.

Description

technical field [0001] The invention belongs to the field of organic synthesis and relates to a Keap1-Nrf2 PPI inhibitor prodrug, in particular to a hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug, a preparation method and a medical application thereof. Background technique [0002] Nuclear transcription factor (Nrf2) acts as a master regulator of multiple cytoprotective responses, playing a key role in the regulation of redox and metabolic homeostasis as well as oxidative stress. Activation of Nrf2 enhances antioxidant capacity and is protective against oxidative stress and inflammatory damage. Recently, therapeutic targets targeting the protein-protein interaction of Nrf2 and its major negative regulator, the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), are emerging as new strategies for drugs to treat chronic diseases. Several pharmaceutical companies and research institutions have reported several PPI inhibitors that effectively disrupt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/14A61P29/00A61K31/426
CPCC07D277/14A61P29/00A61K31/426
Inventor 尤启冬姜正羽陆朦辰张贤赵静郭小可徐晓莉王磊
Owner CHINA PHARM UNIV
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