Use of inhibitors that specifically target the NLRP3 inflammasome

Abstract

We disclose the use of an inhibitor that specifically targets the NLRP3 inflammasome. 5-FUMCL suppressed the secretion of IL-13 and IL-6 in an LPS-induced acute systemic inflammation model, and significantly suppressed the production of inflammatory cytokines IL-1B, IL-6, and IL-18 in acute peritonitis and gouty arthritis induced by intraperitoneal and intra-articular injections of MSU. It also significantly reduced intraperitoneal neutrophil counts and improved knee joint swelling. However, similar anti-inflammatory effects were not observed in models where the NLRP3 molecule was knocked out. These experimental results suggest that 5-FUMCL is a specific inhibitor that targets the NLRP3 inflammasome and can be used as an active ingredient in the manufacture of drugs for the prevention or treatment of NLRP3 inflammasome-related diseases, particularly inflammation-related diseases such as acute systemic inflammation, acute peritonitis, and gouty arthritis.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to an inhibitor specifically targeting the NLRP3 inflammasome, and specifically relates to the anti-inflammatory use of 5-FUMCL.

Background Art

[0002] Inflammation is a self-defense reaction that occurs when an organism is subjected to external invasion or environmental pressure, and plays a very important role in maintaining the health of the body. However, if there is inflammation that cannot be controlled in the body for a long time, it may damage the body and lead to the occurrence of diseases. Since the concept of inflammasome was first proposed by the Tschopp laboratory in 2002, the research on NLRP3 inflammasome has become a field of attention. NLRP3 is composed of three domains: an N-terminal pyrin domain (PYD), a nucleotide-binding oligomerization domain (NACHT) with ATP catalytic function, and a C-terminal leucine-rich repeat (LRR). The host recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), induces the activation of nuclear factor κB (NF-κB), causes the activation of NLRP3, and the activated pyrin-like domain (PYD) of NLRP3 binds to the PYD domain of ASC, associates with the ASC helix to form an ASC spot. Subsequently, the caspase recruitment domain (CARD) of ASC interacts with the CARD of pro-caspase-1, generates caspase-1 through proteolytic cleavage of pro-caspase-1 in the form of an oligomer, and then mediates the processing, maturation and secretion of interleukin IL-1β and IL-18, and regulates the expression of inflammation-related genes, thereby producing various biological effects and causing inflammation. Caspase-1 cleaves gasdermin D (GSDMD) into N-terminal gasdermin-D, forms membrane pores, and causes cell pyroptosis.

[0003] Excessive activation of the NLRP3 inflammasome is associated with a variety of diseases, including cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), inflammatory bowel disease (IBD), type II diabetes, obesity, non-alcoholic steatohepatitis, aging, arteriosclerosis, gout, renal dysfunction, Alzheimer's disease (AD), Parkinson's syndrome, sepsis, endotoxemia, peritonitis, war trauma, cardiovascular stress, and myocardial hypertrophy. It is also associated with various cancers, including colorectal cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, and gastrointestinal cancers.

[0004] The NLRP3 inflammasome is located upstream of inflammatory cytokines and is a key initiator of inflammation-related diseases, making it an important target for the development of novel and specific anti-inflammatory drugs. However, conventional clinical treatments for NLRP3 inflammasome-related diseases, such as IL-18 receptor antagonists, IL-1β neutralizing antibodies, and IL-18 receptor blockers, primarily act by indirectly inhibiting NLRP3 inflammasome components or related signaling events. Although these drugs have achieved good therapeutic effects in clinical practice, their mechanisms of action and precise targets are still not fully understood. Furthermore, activation of the NLRP3 inflammasome not only produces IL-18 and IL-1β, but these inflammatory cytokines may also be produced by the activation of other inflammasomes such as NLRC4 and AIM2, or released through pathways that do not involve the inflammasome. In addition, HMGB1, which is released during cellular pyroptosis, may also be involved in the development and progression of NLRP3 inflammasome-related inflammatory diseases. Therefore, simply inhibiting these downstream inflammatory cytokines carries the risk of off-target effects and may also result in side effects such as immunosuppression. The development of small molecule drugs targeting the NLRP3 inflammasome is significantly lagging. Several biotechnology and pharmaceutical companies are focusing their efforts mainly on the development of NLRP3 inhibitors, but there are still no anti-inflammatory drugs that directly target the NLRP3 inflammasome that are clinically applicable.

[0005] In the search and development of anti-inflammatory drugs that directly target the NLRP3 inflammasome, MCC950 has been shown in studies to be a potential therapeutic agent for NLRP3 inflammasome-related syndromes (including autoinflammatory and autoimmune diseases). Studies have primarily shown that cells pretreated with MCC950 inhibit ASC spot formation under pro-inflammatory conditions. MCC950 also suppresses IL-1β production in the body, reducing the severity of multiple sclerosis disease models such as experimental autoimmune encephalomyelitis (EAE). Furthermore, in CAPS mouse models, treatment with MCC950 reduced neonatal mortality and extended lifespan by approximately 20 days. It also demonstrated an inhibitory effect on plasma IL-18 release in Muckle-Wells syndrome. In the development of a rheumatoid arthritis treatment, MCC950 entered Phase II clinical trials, but these were discontinued due to excessive hepatotoxicity. CN112654350A disclosed a series of NLRP3 antagonists, in addition to MCC950, as treatments for inflammatory or autoimmune diseases. However, these NLRP3 antagonists are still in the development stage and are used in combination therapy with anti-TNFα drugs, clearly lacking the advantages of drugs that directly target NLRP3 itself.

[0006] 5-FUMCL is a sesquiterpenoid derivative represented by the following chemical formula. [ka] Currently, there are no reports on pharmacological studies of 5-FUMCL as an anti-inflammatory drug that directly targets the NLRP3 inflammasome. [Overview of the Initiative]

[0007] (technical issue) The object of the present invention is to provide the use of inhibitors that specifically target the NLRP3 inflammasome.

[0008] (Technical solution) To achieve the above objectives, the present invention employs the following technical solutions.

[0009] This invention provides the use of one or more of 5-FUMCL and its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the manufacture of anti-inflammatory drugs that directly target the NLRP3 inflammasome.

[0010] In a preferred embodiment, the drug is used to prevent or treat inflammatory diseases associated with abnormal activation of the NLRP3 inflammasome.

[0011] In a preferred embodiment, the inflammatory disease associated with the abnormal activation of the NLRP3 inflammasome is one of the following: a hereditary NLRP3-dependent spontaneous inflammatory disease, a metabolic disease caused by NLRP3, a disease caused by crystal and protein aggregation, acute tissue injury, and chronic inflammation.

[0012] In a preferred embodiment, the inflammatory disease associated with the abnormal activation of the NLRP3 inflammasome is one of the following: Cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), inflammatory bowel disease (IBD), type II diabetes mellitus, obesity, non-alcoholic steatohepatitis, aging, tumors, arteriosclerosis, gout, renal dysfunction, Alzheimer's disease (AD), Parkinson's syndrome, sepsis, endotoxemia, peritonitis, war trauma, cardiovascular stress, myocardial hypertrophy, etc.

[0013] In a preferred embodiment, the drug can inhibit the activation of the NLRP3 inflammasome and / or the pyroptosis of cells (such as macrophages).

[0014] In a preferred embodiment, the drug has one or more of the following anti-inflammatory effects: (i) Inhibit the serum secretion of IL-1β, IL-6, and IL-18 induced by LPS and / or MSU; (ii) Inhibit the secretion of IL-1β, IL-6, and IL-18 in the joints and / or ascites fluid induced by LPS and / or MSU; (iii) Inhibit MSU-induced joint swelling; (iv) It inhibits the neutrophil count in the peritoneal fluid induced by MSU.

[0015] In a preferred embodiment, the drug (e.g., a 5-FUMCL-containing drug) can be used for the prevention or treatment of acute systemic inflammation.

[0016] In a preferred embodiment, the drug (for example, a 5-FUMCL-containing drug) can be used for the prevention or treatment of acute peritonitis.

[0017] In a preferred embodiment, the drug (for example, a drug containing 5-FUMCL) can be used for the prevention or treatment of gouty arthritis.

[0018] In a preferred embodiment, the drug (e.g., a 5-FUMCL-containing drug) can inhibit the activation of the NLRP3 inflammasome in vivo and in vitro.

[0019] In a preferred embodiment, the drug includes, in addition to an active ingredient such as 5-FUMCL, a pharmaceutically acceptable carrier and / or other excipients that do not affect the efficacy of the active ingredient. For example, the drug further includes sweeteners to improve taste, antioxidants to prevent oxidation, and excipients necessary for various formulations.

[0020] In preferred embodiments, the dosage form of the drug is not limited and can be any dosage form that allows the active ingredient to effectively reach the body. Examples include common dosage forms such as tablets, capsules, granules, powders, syrups, solutions, suspensions, injections, tinctures, sustained-release formulations, oral solutions, injectable aerosols, lozenges, drinks, pills, pellets, powders, inhaled powder aerosols, or sustained-release dosage forms such as nano-formulations.

[0021] The above-mentioned "pharmaceutically acceptable salt" refers to a salt formed from 5-FUMCL and a pharmaceutically acceptable inorganic acid or organic acid. The inorganic acid is hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid, and the organic acid is formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalenedisulfonic acid, arsenic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid or an amino acid. The above-mentioned "pharmaceutically acceptable" means that there are no excessive side effects (such as toxicity, irritation, and allergic reactions) and it is suitable for human use, that is, there is a reasonable benefit / risk ratio. In pharmacological experiments, usually, the drug substance (for example, 5-FUMCL) is used, and in order to improve the solubility of the drug substance, it is usually pharmacologically possible to convert the drug substance into the form of a salt.

[0022] The above-mentioned "stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in the 5-FUMCL molecule, such as cis-trans isomers, diastereomers, conformational isomers, etc.

[0023] (Beneficial effects) The beneficial effects of the present invention are as follows.

[0024] Through pharmacological experiments, the present invention has clarified that 5-FUMCL can be used in the production of drugs for the prevention and treatment of NLRP3 inflammasome-related diseases. That is, by using 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, etc. as the active ingredient of an anti-inflammatory drug and utilizing its anti-inflammatory effect, it is possible to exert a remarkable therapeutic effect on inflammation-related diseases such as acute systemic inflammation, acute peritonitis, and gouty arthritis without toxic side effects. At the same time, pharmacological experiments have also clarified that 5-FUMCL is an inhibitor that specifically targets the NLRP3 inflammasome.

[0025] Furthermore, the present invention constructed an acute inflammation model by intraperitoneal injection of LPS (lipopolysaccharide) after oral administration of 5-FUMCL, and used MCC950 as a positive control. As a result, it was revealed that 5-FUMCL inhibits the secretion of IL-6 and IL-1β in vivo.

[0026] Furthermore, the present invention can significantly improve the symptoms of gouty arthritis induced by intra-articular injection of MSU (sodium urate) after intraperitoneal injection of 5-FUMCL (reducing the release of inflammatory cytokines in the joint and the degree of joint swelling), but it was also discovered that in a gouty arthritis model with knockout of the NLRP3 molecule, it does not show the corresponding anti-inflammatory effect.

[0027] Furthermore, the present invention can significantly improve the related symptoms of acute peritonitis induced by intraperitoneal administration of MSU after intraperitoneal injection of 5-FUMCL (reducing the release of inflammatory cytokines in the serum and peritoneal cavity and the number of neutrophils), but it was also discovered that in an acute peritonitis model with knockout of the NLRP3 molecule, it does not show the corresponding anti-inflammatory effect.

[0028] Furthermore, the above pharmacological experimental results for various inflammatory disease models indicate that by specifically targeting the activation of the NLRP3 inflammasome, 5-FUMCL can prevent and treat diseases related to abnormal activation of the NLRP3 inflammasome, such as hereditary NLRP3-dependent autoinflammatory diseases, NLRP3-induced metabolic diseases, diseases caused by crystals and protein aggregates, acute tissue injury, and chronic inflammation.

Brief Description of the Drawings

[0029] [Figure 1] Figure 1 shows the experimental results of 5-FUMCL improving LPS-induced systemic inflammation. In the figure, A is the content of IL-6 and IL-1β in the serum 7 hours after LPS administration, and B is the content of IL-6 and IL-1β in the serum 12 hours after LPS administration, where *P < 0.05, **P < 0.01, ***P < 0.001. [Figure 2] Figure 2 shows experimental results demonstrating that 5-FUMCL improves MSU-induced gouty arthritis. In the figure, A is the difference in knee joint width 24 hours after administration to WT mice, B is the content of IL-1β, IL-6, and IL-18 in the joint culture supernatant 24 hours after administration to WT mice, C is the difference in knee joint width 24 hours after administration to NLRP3- / - mice, and D is the content of IL-1β, IL-6, and IL-18 in the joint culture supernatant 24 hours after administration to NLRP3- / - mice, where *P<0.05, **P<0.01, and ***P<0.001. [Figure 3] Figure 3 shows experimental results showing that 5-FUMCL improves MSU-induced acute peritonitis. In the figure, A is the content of IL-1β, IL-6, and IL-18 in the serum of WT mice 6 hours after intraperitoneal injection of MSU. B is the content of IL-1β, IL-6, and IL-18 in the peritoneal fluid of WT mice 6 hours after intraperitoneal injection of MSU. C is the percentage of neutrophils in the cells of the peritoneal fluid of WT mice 6 hours after intraperitoneal injection of MSU. D is the content of IL-1β, IL-6, and IL-18 in the serum of NLRP3- / - mice 6 hours after intraperitoneal injection of MSU. E is the content of IL-1β, IL-6, and IL-18 in the peritoneal fluid of NLRP3- / - mice 6 hours after intraperitoneal injection of MSU. F is the percentage of neutrophils in the peritoneal fluid of NLRP3- / - mice 6 hours after intraperitoneal injection of MSU. Here, *P<0.05, **P<0.01, and ***P<0.001. [Figure 4] Figure 4 shows experimental results regarding the toxicity and side effects of 5-FUMCL.

[0030] (Optimal mode for carrying out the invention) The present invention will be further described below in conjunction with the attached drawings and embodiments. The embodiments described above are used solely for the purpose of illustrating the present invention and do not limit the scope of protection of the present invention.

[0031] (1) Experiments related to the improvement of LPS-induced systemic inflammation by 5-FUMCL a1. Sample preparation 5-FUMCL was dissolved in dimethyl sulfoxide (DMSO) to prepare a 40 mg / mL storage solution. Before intragastric administration, it was diluted with PBS (pH 7.4) to a 0.4 mg / mL working solution, and the experimental in vivo dose of 5-FUMCL was 50 mg / kg. MCC950 was prepared as a storage solution and a working solution at concentrations of 4 mg / mL each with PBS (pH 7.4). The experimental in vivo dose of MCC950 was 50 mg / kg. a2. Experimental method C57BL / 6J mice (n=8 or 6 / group) aged 6-8 weeks and weighing approximately 20g were selected. The experimental group mice were administered 5-FUMCL intragastricly at 50 mg / kg, followed by intraperitoneal injection of LPS at 10 mg / kg 30 minutes later (this group was designated 5-FUMCL+LPS). The blank control group mice were administered an equal amount of PBS intragastricly (this group was designated control), the negative control group mice were administered 5-FUMCL intragastricly only (this group was designated 5-FUMCL), the model group mice were injected with LPS at 10 mg / kg intraperitoneally (i.e., the LPS group), and the positive drug group mice were administered MCC950 intragastricly at 50 mg / kg, followed by intraperitoneal injection of LPS at 10 mg / kg 30 minutes later (this group was designated MCC950+LPS). a3. Method for measuring inflammatory cytokines (refer to the kit instructions for procedure) and statistical methods (one-way ANOVA analysis is used for comparing experimental data between groups). a4, Experimental results As shown in Figure 1, the results in this section indicate that 5-FUMCL can reduce the serum levels of IL-6 and IL-1β, meaning that 5-FUMCL has a protective effect against LPS-induced acute inflammation in mice.

[0032] (2) Experiments on the improvement of MSU-induced systemic inflammation by 5-FUMCL b1. Sample preparation 5-FUMCL was dissolved in dimethyl sulfoxide (DMSO) to prepare a 40 mg / mL storage solution, which was then diluted with PBS (pH 7.4) to a 0.4 mg / mL working solution before injection. The experimental in vivo dose of 5-FUMCL was 50 mg / kg. b2. Experimental Method C57BL / 6J mice, i.e., wild-type mice (n=8 or 6 / group), 6-8 weeks old and weighing approximately 20g were selected. The experimental group mice were intraperitoneally administered 50 mg / kg of 5-FUMCL, and 30 minutes later, 0.5 mg / mice were injected into the knee joint with MSU. 24 hours after MSU injection, the knee joints were excised, cultured in OPTI-MEM medium for 1 hour, and the culture medium was centrifuged to obtain the joint culture supernatant (this group was designated 5-FUMCL+MSU). Blank control mice were intraperitoneally injected with an equal volume of PBS only (this group was designated control). Model mice were injected with 0.5 mg / mice with MSU only into the knee joint (i.e., the MSU group). NLRP3 KO mice (southern model organisms, heterozygous NLRP3 knockout mice obtained using CRISPR / Cas9 technology, and then homozygous NLRP3 knockout mice obtained by subsequent mating), 6-8 weeks old, weighing approximately 20g, i.e., NLRP3 - / - Mice (n=6 / group) were selected. The experimental group mice were administered 50 mg / kg of 5-FUMCL intraperitoneally, followed 30 minutes later by injection of 0.5 mg / mice of MSU into the knee joint. 24 hours after MSU injection, the knee joints were excised, cultured in OPTI-MEM medium for 1 hour, and the culture medium was centrifuged to obtain the joint culture supernatant (this group was designated 5-FUMCL+MSU). The blank control group mice were injected with an equal volume of PBS intraperitoneally (this group was designated control). The model group mice received only MSU injections at 0.5 mg / mice into the knee joint (i.e., the MSU group). b3. Evaluation of knee joint swelling, measurement of inflammatory cytokines, and statistical methods. The maximum width of the knee joint was measured using calipers, knee joint swelling was assessed, inflammatory cytokines were measured according to the kit specifications, and one-way ANOVA analysis was used to compare experimental data between groups. b4, Experimental results As shown in Figure 2, the results in this section indicate that 5-FUMCL improved the MSU-induced arthritis response in WT mice, significantly reducing the content of IL-1β, IL-6, and IL-18 in the joint culture supernatant, and under the same conditions, NLRP3 - / - The protective effect of 5-FUMCL is lost in mice. These results indicate that 5-FUMCL has a significant anti-inflammatory effect against MSU-induced gouty arthritis, and that this anti-inflammatory effect is exerted via the NLRP3 inflammasome.

[0033] (3) Experiments on the improvement of MSU-induced acute peritonitis with 5-FUMCL c1, Sample preparation 5-FUMCL was dissolved in dimethyl sulfoxide (DMSO) to prepare a 40 mg / mL storage solution, which was then diluted with PBS (pH 7.4) to a 0.4 mg / mL working solution before injection. The experimental in vivo dose of 5-FUMCL was 50 mg / kg. MCC950 was prepared as a storage solution and a working solution at concentrations of 4 mg / mL each with PBS (pH 7.4). The experimental in vivo dose of MCC950 was 50 mg / kg. c2, Experimental Method C57BL / 6J mice, 6-8 weeks old and weighing approximately 20g, were selected (n=8 or 6 / group). The experimental group mice were intraperitoneally administered 50 mg / kg of 5-FUMCL, followed 30 minutes later by intraperitoneal injection of 0.5 mg / mice of MSU (this group was designated the 5-FUMCL+MSU group). The blank control group mice were intraperitoneally injected with an equal amount of PBS only (this group was designated the control). The model group mice were intraperitoneally injected with 0.5 mg / mice of MSU (i.e., the MSU group). The positive drug group mice were intraperitoneally administered 50 mg / kg of MCC950, followed 30 minutes later by intraperitoneal injection of 0.5 mg / mice of MSU (this group was designated the MCC950+MSU group). NLRP3 KO mice (southern model organisms, heterozygous NLRP3 knockout mice obtained using CRISPR / Cas9 technology, and then homozygous NLRP3 knockout mice obtained by subsequent mating), 6-8 weeks old, weighing approximately 20g, i.e., NLRP3 - / -Mice (n=6 / group) were selected. The experimental group mice were administered 50 mg / kg of 5-FUMCL intraperitoneally, followed 30 minutes later by intraperitoneal injection of 0.5 mg / mice of MSU (this group was designated 5-FUMCL+MSU). The blank control group mice were administered an equal amount of PBS intraperitoneally (this group was designated control). The model group mice were administered 0.5 mg / mice by intraperitoneal injection of MSU (i.e., the MSU group). C3, neutrophil count, inflammatory cytokine measurement, and statistical methods Neutrophils were detected by flow cytometry, inflammatory cytokines were measured according to the kit specifications, and experimental data between groups were compared using one-way ANOVA analysis. c4, experimental results As shown in Figure 3, the results in this section show that 5-FUMCL significantly reduced the levels of IL-1β, IL-6, and IL-18 in the serum and peritoneal fluid of WT mice after MSU induction, and significantly reduced the percentage of intracellular neutrophils in the peritoneal fluid. Under the same conditions, NLRP3 after MSU induction... - / - The protective effect of 5-FUMCL is lost in mice. These results indicate that 5-FUMCL has a significant anti-inflammatory effect against MSU-induced acute peritonitis, and that this anti-inflammatory effect is exerted via the NLRP3 inflammasome. (4) Toxicity and side effects Mice were intraperitoneally injected with 5-FUMCL at a dose of 50 mg / kg for 120 consecutive days. Liver and pancreas samples were collected and subjected to HE staining, but no obvious inflammatory cell infiltration or damage was observed (Figure 4).

[0034] (5) Preparation of 5-FUMCL inhalation powder aerosol 20 g of 5-FUMCL was mixed with 180 g of excipients (maltodextrin to lactose in a mass ratio of 7:3), then 50% ethanol was added to completely dissolve it. The resulting solution was spray-dried to obtain a powdered aerosol. The powdered aerosol was precisely weighed and filled into No. 3 capsules with a sample amount of 20 mg per capsule. The 5-FUMCL content was 2 mg. The powdered aerosol is highly stable, easy to carry, and easy for patients to administer. Furthermore, because the drug concentration in the lungs is high, systemic drug exposure is reduced, and the therapeutic effect of severe pneumonia can be effectively improved.

[0035] (6) Preparation of 5-FUMCL tablets 10 g of 5-FUMCL was mixed with 87.5 g of excipients (a mass ratio of white dextrin to lactose of 7:3), then 95% ethanol was added, followed by granulation, drying, and sieving of the granules. 2.5 g of sodium stearate was added and thoroughly mixed, and then the mixture was compressed into tablets weighing 100 mg each, with each tablet containing 10 mg of 5-FUMCL.

[0036] (7) Preparation of 5-FUMCL capsules 15 g of 5-FUMCL was mixed with 135 g of excipients (white dextrin to lactose in a mass ratio of 7:3), then 95% ethanol was added, followed by granulation, drying, sieving, and filling into capsules. Each capsule weighed 150 mg, of which 15 mg contained 5-FUMCL.

[0037] (8) Preparation of 5-FUMCL powder injection Dissolve 1 g of 5-FUMCL and 5 g of mannitol in 170 mL of sterile water for injection, mix thoroughly for the first time, then adjust the volume to 200 mL. Filter the resulting solution, fill each vial with 1 mL of the solution, freeze-dry, seal, and sterilize to obtain an injectable powder containing 5 mg of 5-FUMCL per vial.

[0038] (9) Usage and administration Capsules: Adults: Take 2-4 capsules three times a day. Children under 12 years of age: Reduce the dosage by half. Tablets: Adults: Take 3-6 tablets at a time, 3 times a day. Children under 12 years of age: Reduce the dosage by half. Powder for injection: Adults: Administer one vial three times a day by intravenous injection, intravenous drip infusion, or intramuscular injection. Children under 12 years of age: Reduce the dosage by half. [Industrial applicability]

[0039] In summary, the present invention experimentally demonstrated that 5-FUMCL has a remarkable anti-inflammatory effect against LPS-induced acute systemic inflammation, MSU-induced gouty arthritis, and acute peritonitis, and specifically targets the NLRP3 inflammasome. These experimental results show that 5-FUMCL can inhibit the secretion of inflammatory cytokines IL-1β, IL-6, and IL-18 by suppressing the abnormal activation of the NLRP3 inflammasome, exhibiting remarkable clinical efficacy in the prevention and treatment of NLRP3 inflammasome-related inflammatory diseases. In particular, 5-FUMCL can be used as an active ingredient in the manufacture of anti-inflammatory drugs for the treatment of inflammatory diseases such as systemic inflammation, gouty arthritis, and peritonitis.

Claims

1. The use of one or more of 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the manufacture of anti-inflammatory drugs targeting the NLRP3 inflammasome.

2. The following compounds are used to suppress inflammation by targeting the NLRP3 inflammasome: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

3. The following compounds are used to suppress inflammation by targeting the NLRP3 inflammasome: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

4. The use according to claim 1, characterized in that the drug is used to prevent or treat inflammatory diseases associated with abnormal activation of the NLRP3 inflammasome.

5. The following compounds are used to prevent or treat inflammatory diseases associated with abnormal activation of the NLRP3 inflammasome: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

6. The following compounds are used to prevent or treat inflammatory diseases associated with abnormal activation of the NLRP3 inflammasome: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, Any combination of (iii) or (i) and (ii) compounds.

7. The use according to claim 4, 5, or 6, characterized in that the inflammatory disease associated with the abnormal activation of the NLRP3 inflammasome is one of the following: a hereditary NLRP3-dependent spontaneous inflammatory disease, a metabolic disease caused by NLRP3, a disease caused by crystal and protein aggregation, acute tissue injury, and chronic inflammation.

8. The use according to claim 4, 5, or 6, characterized in that the inflammatory disease associated with the abnormal activation of the NLRP3 inflammasome is Cryopyrin-associated periodic syndrome, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, inflammatory bowel disease, type II diabetes, obesity, non-alcoholic steatohepatitis, aging, tumor, arteriosclerosis, gout, renal dysfunction, Alzheimer's disease, Parkinson's syndrome, sepsis, endotoxemia, peritonitis, war trauma, cardiovascular stress, or myocardial hypertrophy.

9. The use according to claim 1, characterized in that the drug inhibits the activation and / or cellular pyroptosis of the NLRP3 inflammasome.

10. The aforementioned drug has one or more of the following anti-inflammatory effects: (i) Inhibit the secretion of IL-1β, IL-6, and IL-18 in the serum; (ii) Inhibit the secretion of IL-1β, IL-6, and IL-18 in the joints and / or ascites; (iii) Inhibit joint swelling; (iv) The use according to claim 1, characterized by inhibiting the number of neutrophils in the peritoneal fluid.

11. The use of one or more of 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the manufacture of drugs for the prevention or treatment of acute systemic inflammation.

12. The following compounds are used to prevent or treat acute systemic inflammation: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, Any combination of (iii) or (i) and (ii) compounds.

13. The following compounds are used to prevent or treat acute systemic inflammation: (i) 5-FUMCL; (ii) Any one of the following: a pharmaceutically acceptable salt, stereoisomer, or precursor compound of 5-FUMCL (iii) or any combination of any multiple compounds from (i) and (ii) above.

14. The use of one or more of 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the manufacture of drugs for the prevention or treatment of acute peritonitis.

15. The following compounds are used to prevent or treat acute peritonitis: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

16. The following compounds are used to prevent or treat acute peritonitis: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

17. The use of one or more of 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the manufacture of drugs for the prevention or treatment of gouty arthritis.

18. The following compounds are used to prevent or treat gouty arthritis: (i) 5-FUMCL; (ii) Any one of the pharmaceutically acceptable salts, stereoisomers, and precursor compounds of 5-FUMCL, (iii) or any combination of any multiple compounds of (i) and (ii) above.

19. The following compounds are used to prevent or treat gouty arthritis: (i) 5-FUMCL; (ii) Any one of the following: a pharmaceutically acceptable salt, stereoisomer, or precursor compound of 5-FUMCL (iii) or any combination of any multiple compounds of (i) and (ii) above.

20. Use of one or more of 5-FUMCL or its pharmaceutically acceptable salts, stereoisomers, and precursor compounds in the inhibition of NLRP3 inflammasome activation.

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