Application of lactic dehydrogenase inhibitor in preparation of medicine for preventing and / or treating aneurysm

Abstract

The invention provides application of a lactic dehydrogenase inhibitor in preparation of a medicine for preventing and / or treating aneurysm. The lactic dehydrogenase inhibitor is selected from a compound shown as a formula I in the specification or pharmaceutically acceptable salt thereof. Experiments show that the lactic dehydrogenase inhibitor can specifically inhibit synthesis of lactic acid in thoracic aortic aneurysm, recover expression of systolic genes, significantly inhibit vascular inflammation, maintain the systolic state of vascular smooth muscle cells and delay progress of thoracic aortic aneurysm. In addition, the lactic dehydrogenase inhibitor can also show a remarkable effect of inhibiting vasodilatation in thoracic aortic aneurysm mice, and has no remarkable influence on normal C57BL / 6J mice, so that the lactic dehydrogenase inhibitor is proved to have targeting and specific effects on thoracic aortic aneurysm. The lactic dehydrogenase inhibitor can also significantly inhibit vascular wall inflammatory response and elastic fiber destruction and delay the progress of thoracic aortic aneurysm by recovering the steady state function of vascular smooth muscle cells.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and relates to a drug for treating cardiovascular diseases, specifically the use of lactate dehydrogenase inhibitors in the preparation of drugs for the prevention and / or treatment of aneurysms. Background Technology

[0002] Thoracic aortic aneurysm and dissection are serious and life-threatening cardiovascular diseases, characterized by the destruction of the aortic media structure, rupture of elastic fibers, and dilation or tearing of blood vessels. Despite significant advancements in surgical techniques, effective drug interventions are still lacking, resulting in high rates of disability and mortality for patients with thoracic aortic aneurysm and dissection.

[0003] Under normal circumstances, vascular smooth muscle cells maintain a contractile phenotype, synthesizing contractile proteins such as actin and myosin to maintain the structural integrity and mechanical tension of the blood vessel wall. However, in the pathological state of thoracic aortic aneurysm and dissection, vascular smooth muscle cells undergo phenotypic transformation, changing from a contractile type to a pro-inflammatory or synthetic type. This leads to the synthesis of large amounts of inflammatory factors and matrix-degrading enzymes, accelerating the destruction of elastic fibers in the aortic media and cell apoptosis, ultimately causing structural instability of the blood vessel wall and the formation of dissection.

[0004] Current aneurysm treatment strategies primarily rely on surgical intervention and blood pressure control. Commonly used drugs include beta-blockers and angiotensin II receptor blockers (ARBs), which have shown some effectiveness in delaying aortic dilation and reducing the risk of rupture. However, existing drugs generally lack direct intervention on core pathological aspects such as vascular wall degeneration, abnormal vascular smooth muscle cell phenotype, and inflammatory responses, making it difficult to reverse or halt the continued progression of the disease. Furthermore, some patients have poor tolerance or adherence to traditional treatments, resulting in limited clinical efficacy. In recent years, research on novel drug delivery systems based on exosomes and nanoparticles has shown strong targeting and tissue penetration capabilities, providing new insights for precision aneurysm treatment. However, their safety, specificity, and long-term efficacy still require extensive clinical validation, and a mature, widely applicable treatment regimen has not yet been established.

[0005] Therefore, there is an urgent need in this field to provide new drugs that can effectively treat aneurysms. Summary of the Invention

[0006] In view of the above-mentioned technical problems in the prior art, the present invention provides the use of lactate dehydrogenase inhibitors in the preparation of medicaments for the prevention and / or treatment of aneurysms. The use of such lactate dehydrogenase inhibitors in the preparation of medicaments for the prevention and / or treatment of aneurysms aims to solve the technical problem of poor efficacy of existing drugs in the treatment of aneurysms.

[0007] This invention provides the use of lactate dehydrogenase inhibitors in the preparation of medicaments for the prevention and / or treatment of aneurysms.

[0008] Furthermore, the aneurysm in question is an arterial dissection aneurysm.

[0009] Furthermore, the lactate dehydrogenase inhibitor is selected from compounds of formula I or a pharmaceutically acceptable salt thereof: Formula I Wherein, R1 is a C1-C4 alkyl group; R4 is selected from the following group: H, C1-C4 alkyl, unsubstituted or -CH2C6H5 with one or two C1-C4 alkyl groups substituted on the benzene ring.

[0010] Furthermore, R1 can be methyl, ethyl, n-propyl, or isopropyl.

[0011] In another preferred embodiment, R1 is n-propyl.

[0012] In another preferred embodiment, R1 is isopropyl.

[0013] Furthermore, R4 is methyl, -CH2C6H5, or -CH2C6H5 with a methyl group substituted on the benzene ring.

[0014] In another preferred example, -CH2C6H5.

[0015] Furthermore, the lactate dehydrogenase inhibitor is selected from compounds of the following group or pharmaceutically acceptable salts thereof:

[0016] FX-11 (Master of Bioactive Molecules; HY-16214).

[0017] Furthermore, the aforementioned purpose is achieved through one or more of the following methods: (a) Inhibits lactate synthesis in thoracic aortic aneurysms; (b) Increase the expression of vascular smooth muscle cell contraction genes and maintain the contractile state of vascular smooth muscle cells; (c) Inhibit vasculitis; and / or (d) Inhibits the destruction of elastic fibers in the blood vessel wall.

[0018] Furthermore, the arteries mentioned are selected from the following group: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, omental artery, inferior mesenteric artery, intracranial artery, carotid artery, or combinations thereof.

[0019] Furthermore, it also contains pharmaceutically acceptable carriers or excipients.

[0020] Furthermore, the drug dosage forms mentioned are injections, powder injections, capsules, tablets, pills, powders, granules, syrups, oral liquids, or tinctures.

[0021] This invention experimentally demonstrates that lactate dehydrogenase inhibitors can specifically inhibit lactate synthesis in thoracic aortic aneurysms, restore contractile gene expression, significantly inhibit vascular inflammation, maintain the contractile state of vascular smooth muscle cells, and delay the progression of thoracic aortic aneurysms. Lactate dehydrogenase inhibitors also showed a significant inhibitory effect on vasodilation in mice with thoracic aortic aneurysms, while having no significant effect on normal C57BL / 6J mice, proving their targeted and specific effects on thoracic aortic aneurysms. Furthermore, lactate dehydrogenase inhibitors can significantly inhibit vascular wall inflammation and elastic fiber damage by restoring the homeostatic function of vascular smooth muscle cells, thereby delaying the progression of thoracic aortic aneurysms. Attached Figure Description

[0022] Figure 1 FX-11 in vitro treatment of mouse vascular smooth muscle cell lines.

[0023] A: ELISA assays showed that in vitro treatment with FX-11 (9 μM, 24h) reduced lactate levels in mouse vascular smooth muscle cells.

[0024] B: RT-qPCR assays showed that FX-11 (9 μM, 24h) maintained the contractile state of vascular smooth muscle cells.

[0025] Figure 2 Survival and disease incidence in normal C57BL / 6J mice treated with FX-11 and mice with a 5-week β-aminopropionitrile (BAPN) diet induced by thoracic aortic aneurysm.

[0026] A: ELISA results showed that in vivo injection of FX-11 (1 mg / kg, three times a week) reduced serum lactate levels in a mouse model of aneurysm.

[0027] B: Stereoscopic examination reveals aortic dilation in each group of mice.

[0028] C: Small animal ultrasound examination of the ascending aortic segment width in mice demonstrated that in vivo injection of FX-11 (1 mg / kg, three times a week) can reduce the aortic width in aneurysm model mice, but does not affect the ascending aortic segment width in normal mice.

[0029] D: Survival curves demonstrate that in vivo injection of FX-11 (1 mg / kg, three times a week) can improve the survival rate of aneurysm model mice, but does not affect the survival rate of normal mice.

[0030] E: Using small animal ultrasound to assess aortic aneurysm formation in mice, it was demonstrated that in vivo injection of FX-11 (1 mg / kg, three times a week) can reduce the incidence of aneurysms.

[0031] Figure 3 Pathological findings in normal C57BL / 6J mice treated with FX-11 and mice with a 5-week β-aminopropionitrile (BAPN) diet induced by thoracic aortic aneurysm.

[0032] A: Paraffin sections of mouse aorta and elastin staining (EVG staining) demonstrated that in mice with thoracic aortic aneurysms treated with FX-11 (1 mg / kg, three times a week), EVG elastin staining of vascular tissue showed a significant reduction in elastic fiber breakage.

[0033] B: Western blot analysis of the aortic media (rich in vascular smooth muscle cells) of mice showed that FX-11 (1 mg / kg, three times a week) treatment in mice with thoracic aortic aneurysms could maintain the contractile phenotype of vascular smooth muscle cells, stabilize the vascular media structure, and thus delay the progression of thoracic aortic aneurysms. Detailed Implementation

[0034] Through extensive and in-depth research, including numerous screenings and tests, the inventors have developed a drug for treating aortic aneurysms. The inventors unexpectedly discovered that compound FX-11 can effectively intervene in the development of thoracic aortic aneurysms by blocking lactate synthesis, restoring vascular smooth muscle cell homeostasis, inhibiting pro-inflammatory phenotypic transformation, and slowing or preventing aortic wall structural damage, thereby fundamentally blocking the aforementioned pathological mechanisms. Through this mechanism of intervention, the invention not only significantly reduces vascular inflammatory responses and matrix metalloproteinase activity, maintaining vascular smooth muscle cell function and vascular media stability, but also possesses high targeting specificity and good safety. This invention provides a non-surgical, mechanism-clear, and target-specific innovative drug intervention for aortic aneurysms, offering a new direction and theoretical basis for clinical treatment of aortic aneurysms. This invention was completed based on this foundation.

[0035] the term Unless otherwise defined, 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 pertains.

[0036] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0037] As used in this article, the terms "room temperature" or "normal temperature" refer to a temperature between 4 and 40 degrees Celsius. o C, preferably, 25±5 oC.

[0038] Aneurysm / Arterial Dissection Aneurysms, especially thoracic aortic aneurysms, are a type of aortic structural disease with a high mortality rate. Their main characteristics include rupture of elastic fibers in the vascular media, loss of smooth muscle cells, weakening of the vessel wall, and localized dilation, which can ultimately lead to aortic rupture or dissection. Due to the insidious onset and rapid progression of thoracic aortic aneurysms, there are currently no effective drug interventions in clinical practice; surgery remains the only definitively effective treatment.

[0039] (1) Surgical intervention is the main treatment method: For established thoracic aortic aneurysms or acute dissections, the current standard treatment is open-chest surgery or transcatheter aortic resection via endovascular repair (TEVAR). Surgery can directly replace the diseased segment of the vessel, effectively preventing rupture and death. However, these procedures are technically demanding, have many complications, and are only suitable for patients who meet the intervention criteria. They cannot stop the progression of early-stage lesions or achieve long-term drug management.

[0040] (2) Antihypertensive therapy as a supportive intervention: To reduce vascular wall tension and slow the progression of aortic dilation, adjuvant antihypertensive drugs such as beta-blockers and angiotensin II receptor blockers (ARBs) are commonly used in clinical practice. Some studies (such as the use of losartan in patients with Marfan syndrome) have shown that these drugs can delay aneurysm expansion, but their mechanisms are mostly based on controlling hemodynamic load and cannot directly reverse degenerative changes in the vascular wall, so their efficacy remains limited.

[0041] (3) Exploratory application of anti-inflammatory and anti-matrix degradation drugs: Inflammatory response and matrix metalloproteinase (MMP)-mediated elastic fiber degradation are key steps in aneurysm formation. Some animal studies have shown that MMP inhibitors (such as doxycycline) or IL-1β and TNF-α antagonists can slow disease progression, but currently no anti-inflammatory or anti-MMP drugs are approved for clinical treatment of TAAD, mainly due to poor targeting and questionable long-term safety.

[0042] (4) Basic research exploration targeting vascular smooth muscle cell homeostasis: Recent basic research has revealed that phenotypic transformation and death of vascular smooth muscle cells are important causes of aortic wall structural damage. Maintaining vascular smooth muscle cell function and preventing its pro-inflammatory transformation have become emerging therapeutic directions, but they are still in the animal experiment or in vitro research stage, and there are no clinically available targeted drugs yet.

[0043] (5) Research on novel drug delivery systems: To improve the precision of interventions, studies have explored delivering anti-inflammatory drugs or RNA interference molecules to aortic lesions via nanoparticles or exosomes. These technologies have shown good local effects and tissue penetration in mouse models, but systemic safety assessments are still lacking, and their clinical application prospects require further validation.

[0044] The main advantages of this invention include: This invention addresses the shortcomings of existing technologies in the treatment of thoracic aortic aneurysms, including a lack of effective drug intervention, insufficient intervention targeting the pro-inflammatory transformation of vascular smooth muscle cells, and a lack of clinical translational basis. It proposes a therapeutic strategy that inhibits lactate metabolism-mediated pro-inflammatory phenotypic transformation of vascular smooth muscle cells, aiming to solve the following technical problems: (1) Blocking lactate synthesis inhibits the pro-inflammatory phenotype transformation of vascular smooth muscle cells: Existing treatments cannot effectively prevent the phenotypic transformation of vascular smooth muscle cells from a contractile to a pro-inflammatory state, leading to degradation and structural damage of elastic fibers in the aortic wall. This invention, by inhibiting lactate dehydrogenase activity and reducing lactate accumulation, fundamentally suppresses the pro-inflammatory state of vascular smooth muscle cells and slows the pathological progression of thoracic aortic aneurysms.

[0045] (2) Improve the targeting and safety of treatment: Addressing the shortcomings of existing anti-inflammatory and anti-matrix degradation drugs, such as poor targeting and significant side effects, this invention precisely regulates the phenotypic transformation mechanism of vascular smooth muscle cells related to lactate metabolism, avoiding immune and metabolic side effects caused by systemic broad-spectrum inhibition, and possesses better tissue targeting and lower risk of adverse reactions.

[0046] (3) Filling the gap in the mechanism of drug treatment for aortic aneurysms: Currently, there are no targeted drugs in clinical practice based on the regulatory mechanisms of lactate metabolism and vascular smooth muscle cell phenotype. This invention is the first to utilize the lactate dehydrogenase inhibitor FX-11 to target and regulate the metabolism and inflammatory phenotype transformation of vascular smooth muscle cells, achieving a mechanistic intervention in thoracic aortic aneurysms. This fills a technological gap in drug treatment in this field and has significant clinical translational value.

[0047] Through the above improvements, this invention solves the core problem of insufficient intervention in the vascular pathological structural damage of thoracic aortic aneurysm by existing technologies, and provides an innovative and more precise treatment method for thoracic aortic aneurysm.

[0048] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0049] Example 1 The purpose of this experiment is to evaluate how FX-11 restores smooth muscle cell contractile function and maintains vascular media stability by inhibiting lactate synthesis.

[0050] The experiment used mice with a 5-week β-aminopropionitrile (BAPN) diet to induce thoracic aortic aneurysm and normal C57BL / 6J mice (Jicui Yaokang). Mice were divided into different groups (sham-operated group + saline group; sham-operated group + FX-11 drug group; model group + saline group; model group + FX-11 drug group, 30 mice in each group). (The dosage of FX-11 was 1 mg / kg, three times a week, equal to the volume of saline). Multiple in vitro and in vivo assays were performed, including ultrasound analysis, vascular structure analysis, and expression of vascular smooth muscle cell contractile genes and pro-inflammatory genes.

[0051] Experimental methods This experiment consists of two parts: in vitro experiments and in vivo experiments. (1) In vitro experiments: Mouse aortic vascular smooth muscle cells (MAVSMCs) were treated with FX-11 (9 μM, 24h) to observe its effect on lactate levels and contraction gene expression in smooth muscle cells.

[0052] (2) In vivo experiments: C57 normal mice (Jicui Yaokang) and mice with a 5-week β-aminopropionitrile (BAPN) diet induced thoracic aortic aneurysm model were treated with FX-11 (1 mg / kg, three times a week), and mouse survival information was recorded. The aortic dilation was detected by vascular ultrasound, and the expression of vascular smooth muscle cell contraction genes and pro-inflammatory genes was detected.

[0053] Experimental results:

[0054] (1) In vitro experiments: After treatment with FX-11, lactate synthesis was significantly inhibited, and the intracellular lactate content decreased ( Figure 1 A). RT-qPCR results showed a significant increase in the expression of vascular smooth muscle cell contraction genes, indicating that FX-11 maintained the contractile state of vascular smooth muscle cells. Figure 1 B).

[0055] (2) In vivo experiments: Aortic dilatation assay: In a mouse model of thoracic aortic aneurysm, FX-11 reduced elevated serum lactate levels associated with aortic aneurysm. Figure 2 A). FX-11 treatment significantly reduced the degree of aortic wall dilation ( Figure 2 BC. Stereoscopic examination reveals aortic dilation in each group of mice. Figure 2 B). Ultrasound results in small animals showed that the width of the ascending aorta decreased from 1.496 mm to 1.292 mm (B). Figure 2C). Further statistics show that the survival rate of the FX-11 treatment group increased from 80% to 93%. Figure 2 D), the incidence of TAAD decreased from 40% to 20%. Figure 2 E). The above results indicate that FX-11 can effectively reduce the incidence and mortality of TAAD and delay disease progression.

[0056] Effects on the aorta of normal mice: When FX-11 was applied to normal C57BL / 6J mice, no significant reduction in aortic width or impact on mouse survival was observed. Figure 2 (BE). This indicates that FX-11 has no effect on the normal aortic wall, further demonstrating its specificity in delaying the progression of thoracic aortic aneurysms, with a significant effect only on mice with thoracic aortic aneurysm models.

[0057] (3) Expression of vascular smooth muscle cell contractile genes and pro-inflammatory genes: In in vivo experiments, EVG elastin staining of vascular tissue in FX-11-treated thoracic aortic aneurysm mice showed a significant reduction in elastic fiber breakage. Figure 3 A). Genes related to the contractile phenotype of vascular smooth muscle cells are synchronously upregulated ( Figure 3 B). These results further confirm that FX-11 can maintain the contractile phenotype of vascular smooth muscle cells, stabilize the vascular media structure, and thus delay the progression of thoracic aortic aneurysms.

[0058] From the above experiments, we can see that: (1) FX-11 as a small molecule inhibitor targets lactate synthesis: FX-11 can specifically inhibit lactate synthesis in thoracic aortic aneurysms, restore the expression of contractile genes, significantly inhibit vascular inflammation, maintain the contractile state of vascular smooth muscle cells, and delay the progression of thoracic aortic aneurysms.

[0059] (2) Specific inhibition of vasodilation: FX-11 showed a significant inhibitory effect on vasodilation in mice with thoracic aortic aneurysm, while no significant effect was observed in normal C57BL / 6J mice, demonstrating its targeting and specific effect on thoracic aortic aneurysm.

[0060] (3) Enhanced by inhibiting lactic acid to promote the contractile state of vascular smooth muscle cells: FX-11 significantly inhibits vascular wall inflammation and elastic fiber damage by restoring the homeostatic function of vascular smooth muscle cells, thus delaying the progression of thoracic aortic aneurysm.

[0061] The above experiments show that the present invention can be further extended as follows: (1) Develop more specific LDHA inhibitors or lactate metabolism intervention molecules. In addition to using the lactate dehydrogenase inhibitor FX-11 to reduce lactate production, this invention also includes the development of structurally optimized LDHA inhibitors, or other metabolic regulatory molecules targeting lactate production and accumulation. These compounds can further reduce lactate levels at the molecular level by improving the specificity of LDHA inhibition, inhibiting the activity of metabolic enzymes in other lactate production pathways, or regulating metabolic flux, thereby achieving metabolic intervention in vascular pathological states. These molecules can be obtained through target prediction, high-throughput screening, or structural optimization, exhibiting greater selectivity and lower toxicity, thus contributing to improved safety and efficacy in the treatment of thoracic aortic aneurysms.

[0062] (2) Other pharmacological intervention strategies for regulating lactate levels This invention also includes other drugs or methods besides FX-11 that can be used to regulate lactate synthesis, clearance, or efflux. For example, by enhancing lactate clearance metabolic pathways (such as pyruvate reoxidation or lactate transport), promoting lactate conversion and utilization (such as activating the lactate-pyruvate cycle), or blocking lactate efflux (such as inhibiting MCT family transporters), the aim of reducing local tissue lactate concentration and improving the smooth muscle cell microenvironment can be achieved. The above intervention strategies can be used alone or in combination with FX-11 to enhance its combined anti-inflammatory and vascular stability-maintaining effects. Through multi-target, multi-pathway lactate regulation schemes, the scope of application and technical protection boundaries of this invention are further expanded.

[0063] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of lactate dehydrogenase inhibitors in the preparation of medicaments for the prevention and / or treatment of aneurysms.

2. The use as described in claim 1, characterized in that, The lactate dehydrogenase inhibitor is selected from compounds of formula I in the following group or a pharmaceutically acceptable salt thereof: Formula I Wherein, R1 is a C1-C4 alkyl group; R4 is selected from the following group: H, C1-C4 alkyl, unsubstituted or -CH2C6H5 with one or two C1-C4 alkyl groups substituted on the benzene ring.

3. The use as described in claim 2, characterized in that, R1 is methyl, ethyl, n-propyl, or isopropyl.

4. The use as described in claim 2, characterized in that, R4 is a methyl group, -CH2C6H5, or -CH2C6H5 with a methyl group substituted on the benzene ring.

5. The use as described in claim 1, characterized in that, The lactate dehydrogenase inhibitors are selected from compounds of the following group or pharmaceutically acceptable salts thereof: #imgpt1# FX-11.

6. The use as described in claim 1, characterized in that, The purpose is achieved through one or more of the following methods: (a) Inhibits lactate synthesis in thoracic aortic aneurysms; (b) Increase the expression of vascular smooth muscle cell contraction genes and maintain the contractile state of vascular smooth muscle cells; (c) Inhibit vasculitis; and / or (d) Inhibits the destruction of elastic fibers in the blood vessel wall.

7. The use as described in claim 1, characterized in that, The arteries mentioned are selected from the following group: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, omental artery, inferior mesenteric artery, intracranial artery, carotid artery, or combinations thereof.

8. The use as described in claim 1, characterized in that, It also contains pharmaceutically acceptable carriers or excipients.

9. The use as described in claim 1, characterized in that, The drug dosage forms are injections, powder injections, capsules, tablets, pills, powders, granules, syrups, oral liquids, or tinctures.

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