Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

1-cyclohexylpyrazolone carboxylesterase 1 inhibitor as well as preparation and application thereof

A technology of cyclohexylpyrazolone carboxylate and cyclohexylpyrazolone, which is applied in the field of 1-cyclohexylpyrazolone carboxylate esterase inhibitors, can solve the problem of reducing drug concentration and affecting bioavailability To achieve the effect of improving drug activity, low cost and reducing cost

Active Publication Date: 2021-01-29
SHANGHAI UNIV OF T C M
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, most prodrugs of carboxylic acid esters, amides, thioesters, and carbamates are hydrolyzed and metabolized by carboxylesterases distributed in the gastrointestinal tract, and are hydrolyzed into water-soluble compounds before being absorbed into the blood. product, reduces the concentration of the drug absorbed into the blood, affecting the bioavailability of

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 1-cyclohexylpyrazolone carboxylesterase 1 inhibitor as well as preparation and application thereof
  • 1-cyclohexylpyrazolone carboxylesterase 1 inhibitor as well as preparation and application thereof
  • 1-cyclohexylpyrazolone carboxylesterase 1 inhibitor as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1. Synthesis of STP1

[0038] The synthetic route of STP1 is as follows figure 1 shown;

[0039] 1) Synthesis of STP1-1:

[0040] At room temperature, NaH (210mmol), dimethyl carbonate (17.6mL, 210mmol), and 30mL toluene were added to a 250mL three-necked flask, and the temperature was raised to 120°C to reflux, and acetophenone (83mmol) in 30mL of toluene was added dropwise. After 30 minutes of reaction, TLC monitored the complete reaction of acetophenone, then added 100 mL of ice water, and adjusted the pH to 6-7 with 6N HCl. Separation, extraction of the aqueous phase with ether (1×100mL, 2×60mL), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, spin-dried the solvent, purified by column chromatography (petroleum ether: ethyl acetate =20:1 elution), a white solid was obtained with a yield of 80-90%.

[0041] 2) Synthesis of STP1-2:

[0042]At room temperature, to a suspension of NaH (15 mmol)...

Embodiment 2

[0098] Quantitative evaluation of the inhibitory ability of 1-cyclohexylpyrazolone compounds on carboxylesterase 1 (hCES1A)

[0099] Using the hydrolytic metabolism of D-luciferin methyl ester (DME) carboxylesterase 1 as a probe reaction, bioluminescence was used to detect the effect of 1-cyclohexylpyrazolone compounds on carboxylic acid with the help of human liver microsome in vitro incubation system IC of esterase 1 (hCES1A) inhibition 50 :

[0100] a) 100 microliters of in vitro metabolic reaction system contains phosphate buffer solution (0.1M PBS, 94 μL) with a pH of 6.5, the final concentration of human liver microsomal protein is 2 μg / mL (HLM, 2 μL), and the final concentration range of inhibitors is 0.1μM-80μM (2μL), shake pre-incubation on a microplate reader for 10 minutes at 37°C;

[0101] b) Add D-fluorescein methyl ester (DME) substrate (2 μL, final concentration 3 μM) to the reaction system to initiate the reaction, and incubate the reaction with shaking on a ...

Embodiment 3

[0104] Quantitative evaluation of the inhibitory ability of 1-cyclohexylpyrazolone compounds on carboxylesterase 2 (hCES2A)

[0105] Using the hydrolytic metabolism of fluorescein diacetate FD (Fluorescein diacetate) as a probe reaction, the effect of 1-cyclohexylpyrazolone compounds on carboxylesterase 2 was determined by means of the in vitro incubation system of human liver microsomes. (hCES1A) inhibited IC 50 :

[0106] a) 200 microliters of in vitro metabolic reaction system containing phosphate buffer solution (0.1M PBS, 194 μL) with a pH of 7.4, the final concentration of human liver microsomal protein is 2 μg / mL (2 μL), and the final concentration range of inhibitors is 0.5 μM -100μM (2μL), shake pre-incubation at 37°C for 5 minutes;

[0107] b) Add FD substrate (2 μL, final concentration 5 μM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 200 μL of acetonitrile and shake vigorously to terminate the reaction;

[0108] c)...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
Login to View More

Abstract

The invention discloses a 1-cyclohexylpyrazolone carboxylesterase 1 inhibitor as well as preparation and application thereof. The structural general formula of the carboxylesterase 1 inhibitor is shown in the specification, wherein R1 and R2 are any one of phenyl, benzyl, 2-methylphenyl, 4-methylphenyl, 4-methylbenzyl and 2-naphthyl respectively. The IC50 for preparing hCES1A reaches 50 nanomoles,and the ratio of the IC50 for inhibiting hCES2A to the IC50 for inhibiting hCES1A can reach 252 times. The inhibitor can improve the oral bioavailability of carboxylic ester exogenous prodrugs by inhibiting the activity of human carboxylesterase subtype 1, or can be used as a synergist of clopidogrel, and can also effectively inhibit the generation of fat cell lipid droplets induced by a mouse preadipose 3T3-L1 cell line. According to the carboxylesterase 1 inhibitor, the raw materials are easy to obtain, the cost is low, the synthesis process is simple, and the yield is high; the inhibitionactivity is high, the selectivity is good, and the application prospect is great.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to a 1-cyclohexylpyrazolone carboxylesterase inhibitor, its preparation and application. Background technique [0002] Carboxylesterase 1 (hCES1A, EC 3.1.1.1) is a serine hydrolase found in liver, small intestine, kidney, lung, testis, heart, monocytes, macrophages and circulating plasma. However, hCES1A is mainly distributed in the liver and exhibits significant tissue-specific distribution. hCES1A is located in the endoplasmic reticulum in subcellular cells, and its C-terminus is responsible for fixing the hCES1A protein to the endoplasmic reticulum, while its active center is located in the protein. N-terminal. Therefore, hCES1A still maintains hydrolysis activity when it is secreted into the cytoplasm or extracellular. As an important hepatic drug-metabolizing enzyme, hCES1A can hydrolyze drugs or ester prodrugs containing ester bonds, such as angioconverting enzyme inhibitor...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/20A61K31/4152A61K31/4365A61K45/06A61P5/50A61P3/10A61P3/06
CPCC07D231/20A61K31/4152A61K31/4365A61K45/06A61P5/50A61P3/10A61P3/06A61K2300/00
Inventor 邹立伟王丹丹钱星凯张静杨凌葛广波金强宋培放
Owner SHANGHAI UNIV OF T C M
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com