CN115350182A

CN115350182A - Application of WZ4141 or pharmaceutically acceptable salt thereof in preparing medicines for treating or relieving inflammation

Info

Publication number: CN115350182A
Application number: CN202210963113.6A
Authority: CN
Inventors: 张仁帅; 龚秋雨; 张广健; 孙建
Original assignee: Qingdao Aike Biotechnology Co ltd; First Affiliated Hospital of Medical College of Xian Jiaotong University
Current assignee: Qingdao Aike Biotechnology Co ltd; First Affiliated Hospital of Medical College of Xian Jiaotong University
Priority date: 2022-08-11
Filing date: 2022-08-11
Publication date: 2022-11-18
Anticipated expiration: 2042-08-11
Also published as: CN115350182B

Abstract

The invention provides an application of WZ4141 or pharmaceutically acceptable salt thereof in preparing a medicine for treating or relieving inflammation, belonging to the technical field of biological medicines, wherein the medicine for treating or relieving inflammation comprises any one of medicines for treating bronchitis, pneumonia, hepatitis, rhinitis, enteronitis, gastritis, nephritis, dermatitis, prostatitis, vaginitis and rheumatoid arthritis. The WZ4141 can be used for treating or relieving inflammation, provides a new application for the WZ4141, and fills up the blank of anti-inflammatory drugs based on PGP-1 targets. The invention also provides a medicament for treating or relieving inflammation.

Description

Application of WZ4141 or pharmaceutically acceptable salt thereof in preparing medicines for treating or relieving inflammation

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to an application of WZ4141 or pharmaceutically acceptable salts thereof in preparing medicines for treating or relieving inflammation.

Background

Inflammation is a defensive reaction process of living tissues having a vascular system to injury factors, and is closely related to various diseases. Research on inflammation and related phenomena (including establishment of an inflammation model, discovery of inflammatory response factors, relationship between the response factors and a drug action mechanism and between inflammation and other diseases and the like) has important guiding significance for drug development and research on various physiological processes.

Proteases are a generic term for a class of enzymes that hydrolyze peptide chains of proteins in vivo, and are of great importance in a variety of physiological processes or diseases. Pyroglutamate aminopeptidase 1 (PGP-1) is a relatively common protease that selectively cleaves pyroglutamic acid residues from the N-terminus of a protein or polypeptide and is commonly used for sequence analysis of proteins in Edman degradation. Early studies showed that Glutamine (Glutamine) at heavy chain ends of Immunoglobulins (Immunoglobulins, especially IgGs) can form Pyroglutamic acid (Pyroglutamic acid) and be cleaved by PGP-1. Leading to degradation of IgGs, PGP-1 is therefore suspected to have a crucial role in inflammatory response processes and their associated diseases. Horse meeting people researchers at the chemical research institute of the Chinese academy of sciences in 2016 are led to find that under the action of Lipopolysaccharide (LPS), PGP-1 in macrophage (RAW 264.7) is highly expressed and has positive correlation with TNF-alpha, and further that PGP-1 is possibly an intracellular inflammation response factor; the research results of Gong Qiuyu doctor, wu Aiguo researchers and the like of the national institute of sciences who produced Ningbo material in 2018 further find that PGP-1 is highly expressed in mouse models of arthritis and acute liver injury, and that the inhibition of PGP-1 in RAW 264.7 cells by Small interfering RNA (Si-RNA) can down-regulate the expression of TNF-alpha in inflammation, prove that PGP-1 may be a potential inflammation factor. Professor Li Lin, nanjing university of industry 5363, 2022, found that PGP-1 is highly expressed in blood and tissues of skin burn patients, and further confirmed that PGP-1 may be used as a biomarker for clinical diagnosis of dermatitis. The current research results show that PGP-1 has an important role in inflammation-related diseases and can be used as a potential brand-new anti-inflammatory drug target. The reasonable drug design based on the PGP-1 target can provide a novel high-efficiency drug for treating inflammatory diseases.

Disclosure of Invention

In order to fill the blank of anti-inflammatory drugs based on PGP-1 targets, the invention provides the application of WZ4141 or pharmaceutically acceptable salts thereof in preparing drugs for treating or relieving inflammation, and the WZ4141 can be used for treating or relieving inflammation, thereby providing a new application for the WZ4141 and simultaneously filling the blank of anti-inflammatory drugs based on PGP-1 targets.

The invention also provides a medicament for treating or relieving inflammation.

The invention is realized by the following technical scheme:

the application provides an application of WZ4141 or a pharmaceutically acceptable salt thereof in preparing a medicine for treating or relieving inflammation, wherein the structural formula of the WZ4141 is as follows:

optionally, the medicament for treating or relieving inflammation comprises a medicament for treating any inflammation of bronchitis, pneumonia, hepatitis, rhinitis, enteronitis, gastritis, nephritis, dermatitis, prostatitis, vaginitis and rheumatoid arthritis.

Based on the same inventive concept, the application also provides the use of WZ4141 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing the content of inflammatory factors.

Further, the inflammatory factor includes at least one of TNF-alpha (tumor necrosis factor alpha), IL-1 beta (interleukin 1 beta), IL-6 (interleukin 6), and IL-10 (interleukin 10).

Based on the same inventive concept, the application also provides a medicament for treating or relieving inflammation, wherein the effective component of the medicament comprises WZ4141 and/or pharmaceutically acceptable salt thereof.

Optionally, the medicament further comprises pharmaceutically acceptable excipients.

Further, the auxiliary materials comprise at least one of a solvent, a propellant, a solubilizer, a cosolvent, an emulsifier, an adhesive, a disintegrating agent, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, a flavoring agent, an anti-adhesive agent, an integrating agent, an osmotic promoter, a pH value regulator, a buffering agent, a plasticizer, a surfactant, a foaming agent, a defoaming agent, a thickening agent, an encapsulating agent, a humectant, an absorbent, a binder, a wetting agent, a diluent, a flocculating agent and a deflocculating agent, a filter aid and a release retardant.

Further, the disintegrating agent comprises at least one of corn starch, potato starch, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and alginic acid; the diluent comprises at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, and crystalline cellulose; the lubricant comprises at least one of superfine silica gel powder, magnesium stearate, calcium stearate, stearic acid, talcum powder and anhydrous silica gel; the adhesive comprises at least one of Arabic gum, gelatin, dextrin, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone; the wetting agent comprises sodium lauryl sulfate; the flavoring agent comprises at least one of aspartame, stevioside, sucrose, maltitol and citric acid; the suspending agent comprises at least one of acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, and aluminum stearate gel; the surfactant comprises at least one of lecithin, sorbitan monooleate and glyceryl monostearate; the preservative comprises methyl paraben and/or propyl paraben.

Optionally, the medicament further comprises a pharmaceutically acceptable carrier.

Optionally, the dosage form of the medicine is any one of tablets, paste, granules, capsules, dispersing agents, sprays and injections.

One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

1. the WZ4141 or the pharmaceutically acceptable salt thereof is used for preparing the medicines for treating or relieving inflammation, the WZ4141 can obviously inhibit PGP-1, and various inflammatory factors including TNF-alpha, IL-1 beta, IL-6 and IL-10 are reduced, so that inflammatory reaction is inhibited.

2. The effective components of the medicine comprise WZ4141 and/or pharmaceutically acceptable salts thereof, the medicine has a significant inhibition effect on PGP-1, and tests on levels of cells and animal models show that the WZ4141 can effectively reduce inflammatory factors TNF-alpha, IL-1 beta, IL-6 and IL-10 of macrophages (J774A.1) and inhibit inflammatory reaction of a lipopolysaccharide-induced rheumatoid arthritis animal model.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.

FIG. 1 is a schematic diagram of the inhibition of PGP-1 protein in inflammatory model cells by WZ4141 of the present invention.

FIG. 2 is a schematic representation of the effect of WZ4141 of the present invention on various inflammatory factors.

FIG. 3 is a graph showing the treatment effect of WZ4141 on arthritis in mice according to the present invention.

Detailed Description

The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.

Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.

Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.

In order to solve the technical problems, the idea of the invention is as follows:

the current research shows that PGP-1 has an important role in inflammation-related diseases, can be used as a potential brand-new anti-inflammatory drug target, and a reasonable drug design based on the PGP-1 target can provide a novel efficient drug for treating inflammation diseases.

Based on this, the present inventors screened and purchased a batch of compounds from Chemdiv database using a virtual computer screening method, and finally obtained N- [3- (1H-pyrrole [2,3-b ] pyridine-4-oxy) phenyl ] acrylamide (CAS: 1222776-76-2, WZ4141) (i.e., WZ 4141) after evaluation through cell and animal experiments. The literature research shows that the compound nitrogen- [3- (1H-pyrrole [2,3-b ] pyridine-4-oxy) phenyl ] acrylamide is not reported as a PGP-1 inhibitor at present, and meanwhile, the compound nitrogen- [3- (1H-pyrrole [2,3-b ] pyridine-4-oxy) phenyl ] acrylamide is not reported for treating inflammation.

The application of WZ4141 or its pharmaceutically acceptable salt in the preparation of a medicament for treating or relieving inflammation will be described in detail with reference to examples and experimental data.

Example 1

Inhibition of PGP-1 by WZ4141

Different concentrations of WZ4141 (0.005nM, 0.01nM,0.1nM,0.5nM,2.5nM,5nM,10nM,100nM,1000nM, 5000nM) were incubated with PGP-1 (0.5U/L) at 37 ℃ for 40 minutes; followed by incubation with a commercial substrate for PGP-1 (L-pyroglutamic acid 2-naphthylamide: 2.5. Mu.M) for 40 minutes at 37 ℃. Absorbance was measured using a UV-2700 UV-visible spectrophotometer (SHIMADZU, japan): wavelength range 200-500nm, slit width 1mm, room temperature measurement. FIG. 1 shows the IC50 values of WZ4141, the IC of PGP-1 inhibition by WZ4141 intracellularly ₅₀ The value was approximately 3.63nM.

Example 2

Inhibition of inflammatory factors by WZ4141

J774A.1 cells (macrophages) were used in the experiment and divided into three groups. Namely, the blank group, which is not treated at all, directly measures the contents of TNF-alpha, IL-1 beta, IL-6 and IL-10. LPS group was stimulated with LPS (lipopolysaccharide: 0,0.2,0.5. Mu.g/mL) at 37 ℃ for 16 hours to measure the contents of TNF-. Alpha.IL-1. Beta., IL-6, IL-10. In the LPS + WZ4141 group, the contents of TNF-. Alpha.IL-1. Beta., IL-6, and IL-10 were measured after stimulating with LPS (lipopolysaccharide: 0,0.2,0.5. Mu.g/mL) at 37 ℃ for 16 hours and then with WZ4141 (1. Mu.M) for 24 hours. As shown in FIG. 2, the compound WZ4141 can significantly inhibit the amounts of inflammatory factors TNF-alpha, IL-1 beta, IL-6 and IL-10.

Example 3

Therapeutic effect of WZ4141 on lipopolysaccharide-induced rheumatoid arthritis in mice

Previous studies have shown that PGP-1 plays an important role in the development and progression of inflammatory diseases. Therefore, the mouse arthritis model induced by lipopolysaccharide is adopted to simulate the pathological manifestations of human rheumatoid arthritis, such as synovial lining cell proliferation, interstitial massive inflammatory cell infiltration, neovascularization of microvessels, pannus formation, cartilage and bone tissue destruction, and the like.

The experiment was divided into control group and administration group, male DBA/1 mice, lipopolysaccharide was completely emulsified with Freund's adjuvant, and 0.2mg was injected intradermally into mice on days 0 and 7. The inflammatory response of the joints usually occurs between days 10 and 13 of the stimulation. The thickness of the sole was measured using a vernier caliper with an accuracy of 0.01mm, and each mouse was scored as the sum of the inflammation score of the toe and the swelling score of the paw (up to 14 points) according to the evaluation of clinical score, and a score of 1.5 was reached as a model construction success, and the mice were randomly regrouped and the following administration experiment was continued.

The scoring criteria were divided into two areas, one was the inflammatory score of the mouse toe and one was the swelling score of the mouse paw, as shown in table 1.

TABLE 1 inflammatory response of the mouse paw joints

Each mouse	Fraction (0-2)	Each claw	Fraction (0-3)
				Toe without inflammation	0	Paw thickness growth < =30% compared to control	0
Toe with inflammation of 1-5 points	0.5	Claw thickness growth > =30% compared to the control	1
				5-10 inflammatory toes	1	Claw thickness growth > =50% compared to the control	2
11-15 inflammatory toes	1.5	Claw thickness growth > =80% compared to the control	3
				More than 15 toe heads with inflammation	2

Inflammation model mice were orally administered compound WZ414110mg/kg twice daily for seven days. Indole Guan Xin, 2mg/kg, was used as the positive control. The results are shown in fig. 3, and the compound WZ4141 can reduce the peak inflammatory reaction of foot joints caused by type II collagen, reduce the level of inflammatory plateau and relieve the level of inflammation in a mouse rheumatoid arthritis model.

Finally, it should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including the preferred embodiment and all changes and modifications that fall within the scope of the invention.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims

Use of wz4141 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or ameliorating inflammation, wherein the WZ4141 has the following structural formula:
2. the use according to claim 1, wherein the medicament for treating or relieving inflammation comprises a medicament for treating inflammation selected from any one of bronchitis, pneumonia, hepatitis, rhinitis, enteronitis, gastritis, nephritis, dermatitis, prostatitis, vaginitis, and rheumatoid arthritis.
Use of WZ4141 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of inflammatory factors.
4. The use according to claim 3, wherein said inflammatory factor comprises at least one of TNF- α, IL-1 β, IL-6 and IL-10.
5. A medicament for treating or relieving inflammation, wherein the effective component of the medicament comprises WZ4141 and/or a pharmaceutically acceptable salt thereof.
6. The medicament for treating or relieving inflammation according to claim 5, wherein the medicament further comprises pharmaceutically acceptable auxiliary materials.
7. The agent for treating or alleviating inflammation according to claim 6, wherein the adjuvant comprises at least one of a solvent, a propellant, a solubilizer, a cosolvent, an emulsifier, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, a fragrance, an anti-adhesive, an integrating agent, an osmotic enhancer, a pH regulator, a buffer, a plasticizer, a surfactant, a foaming agent, an antifoaming agent, a thickener, a coating agent, a humectant, an absorbent, a binder, a wetting agent, a diluent, a flocculating agent and a deflocculating agent, a filter aid, and a release retardant.
8. The medicament for treating or alleviating inflammation according to claim 7, wherein the disintegrating agent comprises at least one of corn starch, potato starch, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, and alginic acid; the diluent comprises at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, and crystalline cellulose; the lubricant comprises at least one of superfine silica gel powder, magnesium stearate, calcium stearate, stearic acid, talcum powder and anhydrous silica gel; the adhesive comprises at least one of Arabic gum, gelatin, dextrin, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone; the wetting agent comprises sodium lauryl sulfate; the flavoring agent comprises at least one of aspartame, stevioside, sucrose, maltitol and citric acid; the suspending agent comprises at least one of acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, and aluminum stearate gel; the surfactant comprises at least one of lecithin, sorbitan monooleate and glyceryl monostearate; the preservative comprises methylparaben and/or propylparaben.
9. The medicament for treating or relieving inflammation according to claim 5, wherein the medicament further comprises a pharmaceutically acceptable carrier.
10. The medicine for treating or relieving inflammation according to claim 5, wherein the dosage form of the medicine is any one of tablets, paste, granules, capsules, dispersing agents, sprays and injections.