Application of small molecule compounds in the preparation of anti-cellular protein toxicity drugs

Abstract

The present invention discloses the application of a small molecule compound in the preparation of an anti-cellular protein toxicity drug. The small molecule compound is specifically nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide, and its structural formula is shown in Formula I. By investigating the effect of the small molecule compound on the paralysis rate of transgenic Caenorhabditis elegans, experimental results show that nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide has a strong anti-cellular protein toxicity activity, can effectively alleviate the symptoms of cell protein poisoning of transgenic nematodes, and delay the paralysis of transgenic Caenorhabditis elegans. Therefore, it is expected to be used in the preparation and development of drugs for treating Alzheimer's disease or neurodegenerative diseases.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to the application of small molecule compounds in the preparation of anti-cell protein toxicity drugs. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease whose pathological features mainly include the formation of amyloid-β plaques, abnormal phosphorylation of Tau protein and neuronal loss. These abnormal processes lead to impaired neuronal function and neural network disorder, ultimately leading to loss of cognitive ability and memory impairment, which imposes a heavy burden on patients and their families. With the intensification of the aging trend of the population, Alzheimer's disease has become a major public health challenge worldwide.

[0003] Cellular protein toxicity plays a key role in the pathogenesis of Alzheimer's disease. Abnormal aggregation of Aβ (β-amyloid protein) and Tau protein not only directly damages neurons, but also triggers a series of harmful biological effects such as intracellular oxidative stress, inflammatory response and mitochondrial dysfunction, ultimately leading to neuronal degeneration and impaired neural network function. Therefore, intervention against cellular protein toxicity has become one of the important strategies for the treatment of Alzheimer's disease. Therefore, the development of drugs against cellular protein toxicity is of great significance.

[0004] Animal models are indispensable tools in the study of Alzheimer's disease. In the process of studying C. elegans, researchers found that C. elegans contains a gene similar to human APP (the source protein of Aβ), apl-1, which is a transmembrane protein in nematodes, but does not contain Aβ sequences. Link CD established an Aβ model of C. elegans by transgenic means. The transgenic nematode model can be used to study the mechanism of AD toxicity, the changes in gene expression caused by Aβ, and explore the efficacy of drugs against AD.

[0005] In addition, studies have shown that drugs against cellular protein toxicity can not only treat Alzheimer's disease, but may also provide new ideas and methods for the treatment of other related neurodegenerative diseases (most of which are caused by cellular protein toxicity).

[0006] So far, there has been no literature report on the pharmacological activity of the small molecule compound, specifically nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide, against cell protein toxicity. Summary of the invention

[0007] In view of the technical problems existing in the background technology, the purpose of the present invention is to provide the use of small molecule compounds in the preparation of anti-cell protein toxicity drugs.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] The first aspect of the present invention provides the use of a small molecule compound in the preparation of an anti-cellular protein toxicity drug, wherein the small molecule compound is nitrogen-[(3S, 4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide, and its structural formula is shown in formula (I):

[0010]

[0011] Preferably, the drug is a pharmaceutical composition consisting of nitrogen-[(3S,4R)-4-(1-methyl-1hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide as an active ingredient and pharmaceutically acceptable excipients.

[0012] The present invention has the following beneficial effects:

[0013] The present invention investigates the effect of a small molecule compound, specifically nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide, on the paralysis rate of transgenic Caenorhabditis elegans, and obtains experimental results showing that nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide has a strong anti-cellular protein toxicity activity, can effectively alleviate the symptoms of cellular protein poisoning of transgenic nematodes, and delay the paralysis of transgenic Caenorhabditis elegans. Therefore, it is expected to be used in the preparation and development of drugs for the treatment of Alzheimer's disease or neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0015] Figure 1 is the structural formula of nitrogen-[(3S,4R)-4-(1-methyl-1hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide;

[0016] Figure 2This figure shows the experimental results of the effect of nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide on the paralysis rate of transgenic Caenorhabditis elegans. DETAILED DESCRIPTION

[0017] In the following description, for the purpose of illustration rather than limitation, specific details such as specific system structures and technologies are provided to provide a thorough understanding of the embodiments of the present invention. However, it should be clear to those skilled in the art that the present invention may also be implemented in other embodiments without these specific details.

[0018] Example 1

[0019] This example uses the CL2006 transgenic nematode model as a model for evaluating the anti-cytoprotein toxicity activity of nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide (specific preparation refers to Chinese patent ZL202211497804.8). The detection steps are:

[0020] (1) Solution preparation

[0021] N-[(3S,4R)-4-(1-methyl-1H-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide was dissolved in DMSO to prepare a sample stock solution with a concentration of 10 mM, and then diluted to a concentration of 100 μM with NGM culture medium.

[0022] (2) Cultivation of CL2006 transgenic Caenorhabditis elegans

[0023] Under laboratory conditions, CL2006 transgenic Caenorhabditis elegans fed on Escherichia coli OP50. A single colony of Escherichia coli was inoculated into LB liquid culture medium and grown at 37°C at 200 rpm for 16 hours. Subsequently, 100 μL of the bacterial solution was added to a 35 mm solid nematode growth medium (NGM) and incubated at room temperature overnight to give it a certain thickness. Subsequently, CL2006 transgenic Caenorhabditis elegans were picked onto NGM dissolved with 100 μM nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide. The control group was added with an equal volume of DMSO and cultured in a biochemical incubator at 20°C.

[0024] (3) Determination of paralysis rate of transgenic Caenorhabditis elegans

[0025] Since nematodes contain apl-1, a gene similar to human APP (the source protein produced by Aβ), which is a transmembrane protein in nematodes but does not contain Aβ sequences, it is necessary to obtain an Alzheimer's disease (AD) model through transgenic methods. CL2006 transgenic nematodes express Aβ in muscle tissue, causing symptoms of paralysis in the nematodes, replicating AD symptoms and pathological changes. Here, nematodes that cannot crawl forward after repeated touches are considered paralyzed, and the percentage of non-paralysis is counted every day. The survival curve and significant differences are drawn using Prism 5 software (Graphpad Software, Inc., San Diego, CA, USA). See the experimental results. Figure 2 .

[0026] Depend on Figure 2 The experimental results show that the transgenic Caenorhabditis elegans in the control group quickly developed paralysis symptoms, while the median time to paralysis of transgenic Caenorhabditis elegans treated with nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide was prolonged by 25%, which was a significant difference ( **** P<0.0001), which shows that the nitrogen-[(3S,4R)-4-(1-methyl-1-hydrogen-pyrazole-5-)-1-[3-(2-naphthyloxy)propyl]-3-pyrrolidinyl]acetamide provided by the present invention can delay the paralysis of transgenic Caenorhabditis elegans and is expected to be used in the development of drugs for the treatment of Alzheimer's disease or various neurodegenerative diseases.

[0027] The present invention is not limited to the above-mentioned specific implementation modes. Various changes made by ordinary technicians in this field based on the above-mentioned concepts without creative work are all within the protection scope of the present invention.

Claims

1. The use of a small molecule compound in the preparation of a drug for treating Alzheimer's disease, characterized in that: The structural formula of the small molecule compound is shown in Formula I: 。 2. Use of the small molecule compound according to claim 1 in the preparation of a drug for treating Alzheimer's disease, characterized in that: The drug is a pharmaceutical composition composed of the small molecule compound described in claim 1 as an active ingredient and pharmaceutically acceptable excipients.

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