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Application of acyl-coenzyme A oxidase as therapeutic target of diabetes

A technology of fatty acyl coenzyme and oxidase, which is applied in the fields of biochemistry and pharmacy, and can solve problems such as no reports of AOX inhibitors

Inactive Publication Date: 2014-11-26
曾嘉
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] There are currently no reports of AOX inhibitors as therapeutic drugs for diabetes

Method used

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  • Application of acyl-coenzyme A oxidase as therapeutic target of diabetes
  • Application of acyl-coenzyme A oxidase as therapeutic target of diabetes
  • Application of acyl-coenzyme A oxidase as therapeutic target of diabetes

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0068] 1. Preparation of AOX inhibitor and its inhibitory effect in vitro

[0069] The present inventors prepared LH-919-CoA. Using LH-919 acid as raw material, high-purity LH-919-CoA was prepared, and its inhibitory effect on AOX was tested. The synthetic method of preparing fatty acyl-CoA from free fatty acid is carried out with reference to literature (Li D. et. al., J. Am. Chem. Soc., 2001, 121, 9034-9042).

[0070] The inventors found for the first time that LH-919-CoA can significantly inhibit liver AOX activity in vitro. First, the recombinantly expressed and highly purified rat liver AOX was used as the target protein to determine the inhibitory effect of LH-919-CoA on AOX. The results showed that LH-919-CoA could rapidly inhibit the activity of AOX, and the inhibitory effect was irreversible. Free LH-919 acid had no inhibitory effect on AOX.

[0071] The rat liver intact peroxisome was used as the test object to test the inhibitory effect of LH-919-CoA on AOX in pe...

Embodiment 1

[0111] Embodiment 1, preparation of AOX inhibitor and in vitro inhibition experiment

[0112] (1) Preparation of AOX inhibitor LH-919-CoA

[0113] The preparation method of LH-919-CoA was carried out according to the literature (Li D. et. al., J. Am. Chem. Soc., 2001, 121, 9034-9042). Specific operation: LH-91920mg (Sigma, St.Louis, MO), add 5mL anhydrous tetrahydrofuran (tetrahydrofuran, THF) (Acros, Geel, Belgium), add 0.1mmol triethylamine (triethylamine) to the solution under nitrogen protection ) (Sigma, St.Louis, MO), after mixing and stirring for 10 minutes, 0.1 mmol isobutyl chloroformate (isobutyl chloroformate) (Acros, Geel, Belgium) was added dropwise to the solution at 0° C., and stirred at room temperature for 1 h. Finally, dissolve 50 mg of coenzyme A sodium salt (Coenzyme A) (USB, Cleveland, OH) in distilled water, add 1 mol / L NaOH to adjust the pH to 8.0, add dropwise to the reaction solution under nitrogen protection, and continue stirring for 20 minutes. Sl...

Embodiment 2

[0131] Example 2. Analysis of the effect of AOX inhibitor precursors on inhibiting AOX in rats and mice

[0132] (1) Experimental determination of the transformation of LH-919 into LH-919-CoA in animals

[0133] Six SPF Wistar rats, male, weighing 220-250 g, were fasted for 12 hours, and the six rats were divided into two groups, the control group and the drug group, with three rats in each group. The control group was given 0.2 mL of olive oil by gavage. In the drug group, LH-919 was dissolved in the corresponding volume of olive oil, 100 μg / kg of LH-919 was intragastrically administered, and all the rats were sacrificed 3 hours later, and the livers were quickly dissected and removed, and immediately placed in liquid nitrogen for preservation.

[0134] The determination of fatty acyl-CoA in subcellular unit contents in liver cells was carried out by reference (Melde K. et. al., Biochem. J., 1991, 274, 395-400). The operation steps are as follows: Accurately weigh 0.3 g of l...

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Abstract

Disclosed are a method for improving metabolic function of mitochondria and use thereof, the method comprising: by inhibiting the in vivo activity of fatty acyl coenzyme A oxidase, activating the adenosine monophosphate activating protein kinase, and promoting mitochondria adipose acidification and mitochondria regeneration in target organs or tissue cells, thereby improving the metabolic function of mitochondria, strengthening insulin sensitivity in the body, and slowing cell ageing. Also disclosed is the use of fatty acyl coenzyme A oxidase inhibitors or fatty acyl coenzyme A oxidase inhibitor precursors in the preparation of drugs for treating diseases related to mitochondrial metabolism dysfunction, such as drugs for diabetes.

Description

technical field [0001] The invention belongs to the fields of biochemistry and pharmacy, in particular, the invention relates to a method for treating diabetes by inhibiting the activity of acyl-CoA oxidase in the body, a fatty acyl-CoA oxidase inhibitor or a precursor of a fatty acyl-CoA oxidase inhibitor Use in the preparation of a medicament for treating diabetes. Background technique [0002] Diabetes mellitus is a syndrome of carbohydrate, fat and protein metabolism disorders caused by the interaction of genetic and environmental factors, relative or absolute lack of insulin, and target tissue insulin resistance. Metabolic disease. If diabetes is not treated effectively, extensive microvascular and macrovascular lesions may occur, and pathological changes in multiple systems such as nerves, urine, and circulation may occur. There are two main types of diabetes: (1) type 1 diabetes, in which pancreatic beta cells are destroyed, usually resulting in absolute insulin def...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K39/395A61P3/10
CPCA61K31/20A61K45/06A61P3/10A61K2300/00
Inventor 曾嘉
Owner 曾嘉
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