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Application of utilizing beta-phenylalanine compounds as aldose reductase inhibitors

A reductase inhibitor, phenylalanine technology, applied in the field of application of β-phenylalanine compounds as aldose reductase inhibitors, can solve problems such as side effects and poor selectivity, and achieve easy synthesis and selection High toxicity, low toxicity effect

Inactive Publication Date: 2012-06-27
广州市爱菩新医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, some drugs in clinical use have side effects and poor selectivity

Method used

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  • Application of utilizing beta-phenylalanine compounds as aldose reductase inhibitors
  • Application of utilizing beta-phenylalanine compounds as aldose reductase inhibitors
  • Application of utilizing beta-phenylalanine compounds as aldose reductase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Virtual Screening

[0035] The specific steps of virtual screening are as follows: figure 1 shown.

[0036] The crystal structures of three aldose reductases with three different binding pockets, which can represent all inhibitor binding pockets, were obtained from the protein crystal structure database. The codes of the proteins are 2PDK, 1US0, and 2FZD. Three crystal structures were processed as follows: water molecules were removed and missing amino acid residues were repaired. Kinetic studies were performed using these three structures as initial structures. Kinetic software uses molecular simulation software package AMBER10 to carry out. The amber molecular force field of FF03 is given to the protein, the GAFF force field is used for the small molecule, and the charge of the small molecule is fitted by the RESP method. Sampling analysis is done after the kinetics is completed, and the cluster analysis method is used to find a reasonable conformation ...

Embodiment 2

[0043] Example 2: Inhibition Test of Aldose Reductase

[0044] Using glyceraldehyde as a substrate, redox reaction occurs under the action of aldose reductase and coenzyme (NADPH), and NADPH is converted into NADP+, which shows the principle that the detectable absorption peak at 340nM in the ultraviolet region decreases. By changing the concentration of the compound to be tested , Measure the absorption peaks of different NADP+ obtained by the catalyzed substrate of aldose reductase after the action of different concentrations of drugs to judge the degree of inhibition of the drug on the enzyme, thereby calculating the IC50 value of the drug on the inhibition of aldose reductase.

[0045] The experiment uses recombinant human aldose reductase, which is obtained through cloning, expression, purification and testing. Glyceraldehyde and NADPH used in the experiment were purchased from Sigma Company. The compounds tested in the experiment were provided by our laboratory. The ex...

Embodiment 3

[0059] Example 3: Selective Inhibition Test of Aldehyde Reductase

[0060] Using glyceraldehyde as a substrate, a redox reaction occurs under the action of aldehyde reductase (ALR1) and coenzyme (NADPH), and NADPH is converted into NADP+, which shows the principle that the detectable absorption peak at 340nM in the ultraviolet region decreases. By changing SYSU- 22363S, SYSU-22433S, SYSU-22439S, SYSU-22449S four compound concentrations, measured the substrates of aldose reductase catalyzed by different concentrations of drugs and obtained different NADP+ absorption peaks to judge the degree of inhibition of the drug on the enzyme, and thus calculated IC50 values ​​of drugs for inhibition of aldehyde reductase. The reaction system is similar to the aldose reductase system, the differences are as follows: no lithium sulfate is added to the system, the test temperature of the system is 37° C., and the concentration of aldehyde reductase used in the system is half of that of aldos...

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Abstract

The invention discloses an application of utilizing beta-phenylalanine compounds as aldose reductase inhibitors. The beta-phenylalanine compounds are used as aldose reductase (ALR2) inhibitors, have the similar enzymology activity of medicine Epalrestat on the market, and show the high selectivity to aldose reductase (EC1.1. 1.2, ALR1) which has very high homology to the ALR2, the cytotoxicity test shows that the compounds have small toxicity. The compounds can be used for preparing medicines for curing or preventing diabetic complications (diabetic cataract, peripheral neuropathy, retinopathy, kidney disease and arterial atherosclerosis). The general formula of the skeleton structure of the beta-phenylalanine compounds is shown in the description: wherein R1, R4 and R5 are hydrogen; R2 and R3 are hydrogen, alkyl, alkoxy, sulfhydryl or halogen; and R6 is naphth, pyrimidyl, pyrazinyl, phenyl, tetrahydro naphthyl or indolyl.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to the application of beta-phenylalanine compounds as aldose reductase inhibitors. Background technique [0002] Diabetes is a syndrome in which the interaction of genetic and environmental factors causes absolute or relative insufficiency of insulin and reduced sensitivity of target tissues to insulin, resulting in metabolic disorders of protein, fat, water and electrolytes. At present, there are 347 million people with diabetes in the world, and 92.4 million in China, accounting for a quarter. Long-term hyperglycemia in diabetic patients can lead to various complications, such as diabetic cataract, peripheral neuropathy, retinopathy, kidney disease, atherosclerosis, etc. The high mortality rate and high disability rate caused by diabetes complications have become serious social problems. Since 2001, World Diabetes Day has focused on the prevention and control of dia...

Claims

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Application Information

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IPC IPC(8): A61K31/197A61K31/4965A61K31/455A61P3/10A61P27/12A61P25/02A61P27/02A61P13/12A61P9/10
Inventor 徐峻王领顾琼
Owner 广州市爱菩新医药科技有限公司
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