WO2024027593A1 - Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途 - Google Patents

Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途 Download PDF

Info

Publication number
WO2024027593A1
WO2024027593A1 PCT/CN2023/109846 CN2023109846W WO2024027593A1 WO 2024027593 A1 WO2024027593 A1 WO 2024027593A1 CN 2023109846 W CN2023109846 W CN 2023109846W WO 2024027593 A1 WO2024027593 A1 WO 2024027593A1
Authority
WO
WIPO (PCT)
Prior art keywords
jun
mice
heart failure
hfpef
model
Prior art date
Application number
PCT/CN2023/109846
Other languages
English (en)
French (fr)
Inventor
王利
李峥
Original Assignee
中国医学科学院阜外医院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医学科学院阜外医院 filed Critical 中国医学科学院阜外医院
Publication of WO2024027593A1 publication Critical patent/WO2024027593A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to the use of a Jun inhibitor for the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • Heart failure is the main cause of death in patients with cardiovascular disease and is also a major clinical problem.
  • Heart failure includes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).
  • HFpEF cardiovascular disease 2019
  • HFpEF cardiovascular disease 2019
  • HFpEF cardiovascular disease 2019
  • HFpEF is a comprehensive disease involving multiple organ disorders. The symptoms and results are caused by the heart, lungs, kidneys, bones, immunity, inflammation, metabolism and other components. It is often accompanied by symptoms such as obesity, hypertension, myocardial hypertrophy, diabetes or atrial fibrillation. .
  • HFpEF is a syndrome with high morbidity and mortality. According to clinical statistics, the mortality rate due to HF is 35%, and HFpEF accounts for 57% of the deaths. But to date, few current drug therapies or medical devices have been proven to change disease progression and prognosis in patients with HFpEF. At present, there is an urgent need in this field to develop a drug and/or treatment method that can effectively treat HFpEF.
  • Jun is a transcription factor and a member of the AP1 family. It has chromatin binding activity and transcription cis-regulatory region binding activity. It participates in the regulation of processes including animal organ development, protein phosphorylation, and cell proliferation.
  • Jun inhibitors refer to inhibitors that can inhibit the expression of Jun gene, reduce the binding activity of Jun to DNA, reduce the level of Jun gene expression products, or prevent or block Jun signal transduction. Current studies have shown that Jun inhibitors have therapeutic effects in animal models such as endometriosis, breast cancer, and sepsis.
  • the inventor of the present invention discovered for the first time that using Jun inhibitors to inhibit the high expression of Jun can The present invention was completed by exerting preventive and therapeutic effects on HFpEF.
  • the technical solution of the present invention includes: the use of Jun inhibitors for the treatment or prevention of heart failure with preserved ejection fraction (HFpEF).
  • the Jun inhibitor is selected from the group consisting of T-5224, MLN44, SR11302, Veratramine, KCR motif peptide-1- ⁇ N-[2-succinimidylethyl]amino ⁇ anthraquinone, NY2267 , cFos LZ, anti-Jun, anti-Fos SZ, FosW, FosWCANDI, CPW, FosUisCan, A-Fos, JNK Inhibitor VIII, IQ3, Tanzisertib (CC-930), or pharmaceutically acceptable salts of the above substances.
  • the above substances have been reported to have Jun inhibitor activity, and their structures are as follows:
  • the Jun inhibitor is T-5224 or a pharmaceutically acceptable salt thereof.
  • Figure 1 Construction of the HFpEF model.
  • A Schematic diagram of experimental flow; B: Mice shrink after 5 weeks of feeding Function test results; C: Diastolic function test results of mice fed for 5 weeks.
  • FIG. 1 Relative expression of Jun in cardiomyocytes after 15 weeks of HFD+L-NAME feeding, indicating that Jun is highly expressed in HFpEF model mice.
  • T-5224 can effectively alleviate the occurrence and development of HFpEF.
  • “CHOW” represents the normal group of mice
  • “HFD+L-NAME” represents the model control group of mice
  • “HFD+L-NAME+T-5224” represents the model administration group of mice.
  • “CHOW” represents the normal group of mice
  • “HFD+L-NAME” represents the model control group of mice.
  • the histograms at each time point are represented by “CHOW” and “HFD+L- NAME” and "HFD+L-NAME+T-5224" are arranged from left to right.
  • C57BL/6N wild-type mice were purchased from Beijing Vitong Lever. Sources of reagents are listed in the table below.
  • mice Eight to ten weeks old male C57BL/6N wild-type mice were divided into three groups, namely the normal group (normal diet and water), and the model control group (high-fat diet combined with N-nitro-L-arginine methyl ester) and model treatment group (high-fat diet combined with N-nitro-L-arginine methyl ester and treated with T-5224).
  • the model control group and the model treatment group were modeled in the following ways: Gabriele G. Schiattarella et al., Nitrosative stress drives heart failure with preserved ejection fraction, https://doi.org/10.1038/s41586-019- 1100-z .
  • HFD high-fat diet
  • L-NAME N-nitro-L-arginine methyl ester
  • the systolic function parameter LVEF of the mice did not change during the fifth week of model induction, while the diastolic function parameter (E/E') increased significantly at the fifth week of model induction, indicating that the parameters recorded in the aforementioned literature have been successfully obtained.
  • diastolic function parameters (E/E') there was no significant difference in diastolic function parameters (E/E') between the model control group and the model treatment group at five weeks. Subsequent drug treatment was performed under the same baseline conditions, as shown in Figure 1 Show.
  • mice were injected with 100 ⁇ l of heparin sodium (1000 units in 50 ml) 20 minutes before sacrifice to prevent cardiac coagulation during the operation and increase the difficulty of digestion. Afterwards, the mice were anesthetized, sacrificed, and the hearts were removed and transferred to Wash in calcium-free solution, and then digest using Langendorff's method. Use Langendorff device to perfuse the heart with calcium-free solution for 5 minutes, and then use digestive enzyme solution (0.7 mg/ml type II collagenase and 0.7 mg/ml bovine serum albumin). Calcium-free solution) digest for about 30 minutes. Keep touching the heart for about 20 minutes.
  • the heart becomes soft and slippery, it indicates that digestion is basically complete. Then collect the tissue from the ventricle, cut it into pieces, and dissociate it into single cells by gentle pipetting. Let it stand for sedimentation. Take the supernatant, remove the undigested and adherent tissue, and centrifuge it at 100g for 2 minutes at 4°C to obtain the cardiomyocyte pellet. Most of the clear cells are non-myocardial cells.
  • the cardiomyocytes are resuspended in calcium-free solution containing 10% FBS for subsequent experiments. The non-myocardial cells can be re-selected in culture medium or PBS for subsequent experiments. If you want to obtain more pure myocardium. Cells and non-cardiomyocytes, the cell suspension can be centrifuged (100g, 2 minutes at room temperature) three times to separate cardiomyocytes from non-cardiomyocytes. Cardiomyocytes were collected for further experiments.
  • mice in the model treatment group were treated with T-5224, and the model control group was treated with drug-free solvent, and normal conditions were applied during the entire induction process. Mice on diet and water served as negative controls. The mice were administered when they were raised for 5 weeks.
  • T-5224 was administered at 250 mg/kg according to the mouse body weight. Specifically, it was administered every other day.
  • mice were fed under different conditions for five weeks and then underwent routine ultrasound testing every two weeks until the end of fifteen weeks of testing. Specifically, transthoracic echocardiography was performed using a VisualSonics Vevo 2100 system equipped with an MS400 transducer (Visual Sonics). Left ventricular ejection fraction (LVEF) and other measures of systolic function were obtained from short-axis M-mode scans at the midventricular level, as indicated by the presence of papillary muscles, in conscious, lightly restrained mice. Apical four-chamber views were obtained in anesthetized mice for diastolic function measurements at the mitral valve level using pulsed wave and tissue Doppler imaging.
  • LVEF Left ventricular ejection fraction
  • systolic function were obtained from short-axis M-mode scans at the midventricular level, as indicated by the presence of papillary muscles, in conscious, lightly restrained mice. Apical four-chamber views were obtained in anesthetized mice for diastolic function measurements at the mitral valve
  • Parameters collected include: heart rate, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, end-diastolic septal wall thickness, left ventricular end-diastolic posterior wall, left ventricular fractional shortening, LVEF, Doppler peak early diastolic crossing Mitral valve velocity, peak Doppler flow velocity across the mitral valve in late diastole, isovolumic relaxation time, peak tissue Doppler velocity of myocardial relaxation at the mitral annulus during early diastole and early filling deceleration time. At the end of the procedure, all mice recovered from anesthesia without any abnormalities. All parameters were measured at least 3 times and average values were given. Ultrasound testing includes systolic function and diastolic function testing.
  • T-5224 was used to verify the effectiveness of Jun inhibitors in preventing and treating HFpEF. After confirming that the model construction is successful and that the baselines of the model control group and the model treatment group are consistent, the model treatment group is treated with T-5224.
  • the cardiac function test results show that the model treatment group (T-5224 administration treatment The occurrence and development of HFpEF have been well suppressed, which is specifically reflected in the diastolic relaxation of mice treated with high-fat diet combined with L-NAME (HFD+0.5g/L L-NAME) after treatment with T-5224.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明涉及Jun抑制剂在制备用于治疗射血分数保留的心衰(HFpEF)的药物中的用途。

Description

Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途 技术领域
本发明涉及Jun抑制剂在制备用于治疗射血分数保留的心衰(HFpEF)的药物中的用途。
背景技术
心血管疾病代表着医学挑战的难题之一，心力衰竭(heart failure,HF)是心血管疾病患者死亡的主要原因，也是临床面临的一大难题。心力衰竭包括射血分数降低的心力衰竭(heart failure with reduced ejection fraction，简称HFrEF)和射血分数保留的心力衰竭(heart failure with preserved ejection fraction，简称HFpEF)。
目前HFpEF占所有心力衰竭患者约50％，并且其患病率正以惊人的速度增长，也是导致心血管疾病死亡率上升的主要原因。HFpEF是涉及多器官障碍的综合病症，是心脏、肺、肾、骨骼、免疫、炎症、代谢和其他成分共同导致症状和结果，常伴有肥胖、高血压、心肌肥大、糖尿病或房颤等症状。HFpEF是一种高发病率和高死亡率的综合征，据临床统计因HF的死亡率为35％，HFpEF所导致的死亡比例占其中的57％。但是迄今为止，临床上目前很少有药物疗法或医疗设备被证明可以改变HFpEF患者的疾病进展和预后。目前本领域亟待开发一种能够有效治疗HFpEF的药物和/或治疗方法。
Jun是一种转录因子，为AP1家族成员之一，具备染色质结合活性以及转录顺式调控区域结合活性，参与调控包括动物器官发育、蛋白质磷酸化和细胞增殖等过程。Jun抑制剂是指其能够抑制Jun基因的表达、降低Jun与DNA的结合活性、降低Jun基因的表达产物水平、或阻止或阻断Jun的信号转导的抑制剂。目前已有研究表明Jun抑制剂在子宫内膜异位症、乳腺癌、脓毒症等动物模型中具有治疗作用。
发明内容
本发明的发明人首次发现，使用Jun抑制剂对Jun的高表达进行抑制能够 对HFpEF产生预防和治疗的作用，由此完成了本发明。
因此，本发明的技术方案包括：Jun抑制剂在制备用于治疗或预防射血分数保留的心力衰竭(HFpEF)的用途。
在一个优选的实施方案中，所述Jun抑制剂选自T-5224、MLN44、SR11302、Veratramine、KCR模体肽-1-{N-[2-琥珀酰胺基乙基]氨基}蒽醌、NY2267、cFos LZ、anti-Jun、anti-Fos SZ、FosW、FosWCANDI、CPW、FosUisCan、A-Fos、JNK Inhibitor VIII、IQ3、Tanzisertib(CC-930)，或以上物质的药学上可接受的盐。上述物质均已被报导具有Jun抑制剂活性，其结构如下所示：

(注：以上表示NHX的各序列中，字母为氨基酸的单字母缩写)

在一个更优选的实施方案中，所述Jun抑制剂为T-5224或其药学上可接受的盐。
附图说明
图1：HFpEF模型的构建。A：实验流程示意图；B：小鼠喂养5周后收缩 功能的检测结果；C：小鼠喂养5周后舒张功能的检测结果。
图2：HFD+L-NAME喂养15周之后心肌细胞Jun的相对表达量，表明Jun在HFpEF模型小鼠中高表达。
图3：T-5224可以有效缓解HFpEF的发生发展。A：不同时间点小鼠收缩功能的检测结果；B：不同时间点小鼠舒张功能的检测结果；C：不同处理小鼠体重的变化；D：不同处理小鼠心肌细胞Jun的表达量变化。
图1-3中，“CHOW”均代表正常组小鼠，“HFD+L-NAME”均代表模型对照组小鼠，“HFD+L-NAME+T-5224”均代表模型给药组小鼠。在图3A至C中，“CHOW”均代表正常组小鼠，“HFD+L-NAME”均代表模型对照组小鼠，每个时间点的柱状图均以“CHOW”、“HFD+L-NAME”、“HFD+L-NAME+T-5224”的顺序从左至右排列。
具体实施方案
通过以下实施例对本发明的具体实施方案进行例示，并验证本发明所取得的效果。应理解下述实施例仅起到例示作用，本发明的技术方案不限于该实施例。
实施例
1.材料及试剂
在本实施例中，C57BL/6N野生型小鼠购自北京维通利华。试剂的来源如下表所示。
除上述外，本实施例所用的其它材料和试剂也均为市售产品。
2.动物实验准则
本实施例中，所有动物研究均根据中国国家心血管病中心阜外医院动物保健和使用委员会实验动物中心的指导下进行。所有小鼠均在同一环境下进行扩繁和饲养，实验过程将小鼠随机分组。超声心动图分析由不知道研究目标的的独立研究者进行。
3.射血分数保留的心衰模型诱导
八周龄到十周龄雄性C57BL/6N野生型小鼠被分为三组，即正常组(正常饮食饮水)，模型对照组(高脂饮食配合给予N-硝基-L-精氨酸甲酯)和模型治疗组(高脂饮食配合给予N-硝基-L-精氨酸甲酯，并用T-5224处理)。其中，模型对照组和模型治疗组通过以下文献记载的方式进行造模：Gabriele G.Schiattarella等人，Nitrosative stress drives heart failure with preserved ejection fraction，https://doi.org/10.1038/s41586-019-1100-z。具体地，使用高脂饮食(HFD)(60％千卡，来自脂肪(猪油))和N-硝基-L-精氨酸甲酯(缩写为L-NAME，于饮用水中0.5g/L)的方式来诱导射血分数保留的心衰，得到HFpEF动物模型。
在模型诱导第五周检测小鼠的收缩功能参数LVEF并没有发生变化，而舒张功能参数(E/E’)在模型诱导第五周时显著升高，表明已成功获得了前述文献所记载的射血分数保留的心衰模型，同时，五周时模型对照组和模型治疗组舒张功能参数(E/E’)无显著区别，在基线相同的情况下进行后续给药处理，如图1所示。
4.Jun的表达与HFpEF存在相关性
在模型诱导到15周的时候，采用灌流的方法将正常组和模型对照组小鼠的心肌细胞提取分离，进行定量RCR检测具体操作如下：
4.1.成年鼠心肌细胞分离：
为了从成年小鼠心脏中分离心肌细胞，我们采用经典的灌流的方法分离心肌细胞。具体小鼠在处死前20分钟向小鼠注射100μl肝素钠(在50ml中1000个单位)以防止操作过程中心脏凝血增大消化难度，之后，将小鼠麻醉，处死，取出心脏将心脏转移到无钙液中进行洗涤，之后使用Langendorff的方法进行消化，使用Langendorff装置用无钙液灌注心脏5分钟，然后用消化酶液(0.7mg/ml II型胶原酶和0.7mg/ml牛血清白蛋白无钙液)消化大约30分钟，大约20分钟的时候不断去触碰心脏，当心脏变软变滑表明消化基本结束，之 后收集来自心室的组织，剪碎，并轻轻吹打解离成单个细胞，静置沉降，取上清，去掉没消化的及粘连的组织，100g 4℃离心2分钟，得到心肌细胞沉淀，上清则大部分为非心肌细胞，心肌细胞用含有10％FBS的无钙液重悬，用于后续实验，非心肌细胞可以用培养基或者PBS重选用于后续实验，如果为了得到更纯的心肌细胞和非心肌细胞，可以将细胞悬浮液离心(100g，室温下2分钟)三次，以将心肌细胞与非心肌细胞分离。收集心肌细胞用于进一步的实验。
4.2.定量PCR检测：
使用GeneJet RNA纯化试剂盒(Thermo Scientific，K0732)从细胞中提取总RNA，并使用iScript TM cDNA合成试剂盒(Bio-Rad，1708890)逆转录0.1μg总RNA以产生cDNA，使用ABI Vii7实时系统(Life Technologies，Q6)上的iTaqUniversl SYBR Green supermix(1725121，Bio-Rad)进行qPCR，b-Actin，用于标准化定量分析。如图2所示，与正常组小鼠对比，在小鼠HFpEF动物模型中显著地观察到Jun的高表达。这表明，在小鼠中Jun的表达量与HFpEF存在相关性，在HFpEF中，Jun是高表达的。
5.T-5224给药方法
在获得动物模型后，即自诱导HFpEF模型的第五周起，对模型治疗组使用T-5224对小鼠进行处理，对模型对照组用不含药物的溶剂进行对照处理，诱导全程同时加以正常饮食和饮水的小鼠作为阴性对照。小鼠饲养到5周的时候进行给药处理，对于处理组，T-5224按照250mg/kg根据小鼠体重进行给药，具体是隔天给药，每次把0.8mg的T-5224溶在200uL的1％PVP溶液中，从第五周开始给药，到第十三周结束(共计给药15次)，总量给到250mg/kg；对照组给等体积的1％PVP溶液，除此以外其它处理方式相同。
6.常规超声检测
所有小鼠在不同条件下喂养五周之后开始进行常规超声检测，每隔两周测一次，一直到十五周检测结束。具体地，使用配备MS400换能器(Visual Sonics)的VisualSonics Vevo 2100系统进行经胸超声心动图。左心室射血分数(LVEF)和其他收缩功能指标是从心室中部水平的短轴M型扫描获得的，如乳头肌的存在所表明的，在有意识的、轻轻约束的小鼠中。在麻醉小鼠中获得心尖四腔视图，用于在二尖瓣水平使用脉冲波和组织多普勒成像进行舒张功能测量。麻醉由2.5％异氟醚诱导，并通过对其中一只后爪上的坚定压力缺 乏反应来证实。在超声心动图采集期间(在体温控制条件下)异氟烷降低至1.0-1.5％，并进行调整以将心率保持在每分钟500次的范围内。收集的参数包括：心率、左心室舒张末期直径、左心室收缩末期直径、舒张末期室间隔壁厚度、左心室舒张末期后壁、左心室缩短分数、LVEF、多普勒血流峰值舒张早期穿过二尖瓣的速度、舒张晚期穿过二尖瓣的峰值多普勒血流速度、等容舒张时间、舒张早期和早期充盈减速时间二尖瓣环处心肌松弛速度的组织多普勒峰值。在程序结束时，所有小鼠都从麻醉中恢复过来，没有任何异常。所有参数至少测量3次，并给出平均值。超声检测包括收缩功能及舒张功能检测。
7.实验结果及结论
首先，5周时对小鼠的收缩功能和舒张功能进行检测，收缩功能无明显变化，但舒张功能参数E/E’显著升高，证明舒张功能存在障碍，表明成功获得了如前述文献所记载的模型。同时以第5周作为给药起点，模型对照组和模型治疗组在给药前心脏舒张功能无明显差异(图1A-C)，在此基础上进行给药处理。
其次，对比正常组、模型对照组Jun的表达显示上调，说明Jun的表达与HFpEF的相关性，在HFpEF小鼠模型中，Jun是高表达的(图2)。基于这种相关性，可以判断Jun抑制剂能够用于HFpEF的预防和治疗。
进一步地，使用T-5224来验证Jun抑制剂预防和治疗HFpEF的效果。在确定模型构建成功的情况下，且模型对照组和模型治疗组基线一致的条件下，用T-5224对模型治疗组进行处理，心脏功能检测结果表明，模型治疗组(T-5224给药处理后)中HFpEF的发生发展都得到了很好的遏制，具体体现在使用T-5224处理后，利用高脂饮食配合L-NAME处理(HFD+0.5g/L L-NAME)处理的小鼠舒张功能显著改善，并可以一直持续到第十五周；但在没有用T-5224处理的模型对照组小鼠中，则观察到舒张功能的持续恶化(图3A-B)；同时，模型治疗组中，Jun的表达相比模型对照组是下调的(图3D)，并且小鼠肥胖有得到改善(图3C)。这表明作为Jun抑制剂的T-5224能够在小鼠HFpEF模型中对HFpEF产生预防和治疗的作用。

Claims (3)

  1. Jun抑制剂在制备用于治疗或预防射血分数保留的心衰的药物中的用途。
  2. 根据权利要求1所述的用途，其中所述Jun抑制剂选自T-5224、MLN44、SR11302、Veratramine、KCR模体肽-1-{N-[2-琥珀酰胺基乙基]氨基}蒽醌、NY2267、cFos LZ、anti-Jun、anti-Fos SZ、FosW、FosWCANDI、CPW、FosUisCan、A-Fos、JNK Inhibitor VIII、IQ3、Tanzisertib(CC-930)，或以上物质的药学上可接受的盐。
  3. 根据权利要求2所述的用途，其中所述Jun抑制剂选自T-5224或其药学上可接受的盐。
PCT/CN2023/109846 2022-07-30 2023-07-28 Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途 WO2024027593A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210911679.4 2022-07-30
CN202210911679.4A CN117503932A (zh) 2022-07-30 2022-07-30 Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途

Publications (1)

Publication Number Publication Date
WO2024027593A1 true WO2024027593A1 (zh) 2024-02-08

Family

ID=89746310

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/109846 WO2024027593A1 (zh) 2022-07-30 2023-07-28 Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途

Country Status (2)

Country Link
CN (1) CN117503932A (zh)
WO (1) WO2024027593A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018169742A1 (en) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Apoptosis signal-regulating kinase inhibtor
JP2020189828A (ja) * 2019-05-17 2020-11-26 国立大学法人 岡山大学 外用剤組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018169742A1 (en) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Apoptosis signal-regulating kinase inhibtor
JP2020189828A (ja) * 2019-05-17 2020-11-26 国立大学法人 岡山大学 外用剤組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAKAMURI SIVA S.V.P., VALENTE ANTHONY J., SIDDESHA JALAHALLI M., DELAFONTAINE PATRICE, SIEBENLIST ULRICH, GARDNER JASON D., BYSANI: "TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis", MOLECULAR AND CELLULAR ENDOCRINOLOGY, ELSEVIER IRELAND LTD, IE, vol. 429, 1 July 2016 (2016-07-01), IE , pages 84 - 92, XP093135237, ISSN: 0303-7207, DOI: 10.1016/j.mce.2016.03.038 *

Also Published As

Publication number Publication date
CN117503932A (zh) 2024-02-06

Similar Documents

Publication Publication Date Title
Wang et al. The ACE2-Ang (1-7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction
TWI794885B (zh) 全身紅斑性狼瘡之治療
JP2002544210A (ja) 炎症で仲介される感染症に対する抗炎症性治療方法
BARATOVA et al. Modern Ultrasound Methods for Assessing Indicators of The Latent Diastolic Function of The Left Ventricle.
WO2024027593A1 (zh) Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途
Van der Leij et al. Successful outcome of pregnancy after treatment of maternal anti‐Ro (SSA) antibodies with immunosuppressive therapy and plasmapheresis
CN108143735A (zh) 毛壳素在制备预防和治疗低氧性肺动脉高压药物中的应用
Sugimoto et al. Autophagy during left ventricular redilation after ventriculoplasty: Insights from a rat model of ischemic cardiomyopathy
JP7231543B2 (ja) 心不全および心臓虚血再灌流障害の治療
Hashmi et al. Cardiogenic shock: a rare complication of influenza
Sheba et al. Nonalcoholic fatty liver disease is associated with early left ventricular diastolic dysfunction in patients with type 2 diabeteS
CN115463134B (zh) 一种sirt2特异性抑制剂ak-1的应用
Kıztanır et al. Fetal and postnatal diagnosis and management of cardiac rhabdomyomas and association with tuberous sclerosis complex
He et al. S-adenosyl-L-methionine improves ventricular remodeling after myocardial infarction by regulating angiogenesis and fibrosis
CN114504650B (zh) Lgmn作为靶点在治疗缺血性心脏病中的应用
Lopez et al. AB0799 REAL-WORLD EXPERIENCE OF SECUKINUMAB FOR PSORIATIC ARTHRITIS WITH AXIAL INVOLVEMENT.
Lanzillo et al. Interferon-Beta and Pulmonary Artery Hypertension: Case Reports and Review of the Literature
Markelova AB0798 EFFECT OF ANTIRHEUMATIC THERAPY ADMINISTERED IN ACCORDANCE WITH “TREAT TO TARGET” PRINCIPLES ON DIASTOLIC DYSFUNCTION OF THE LEFT VENTRICLES IN PATIENTS WITH ACTIVE EARLY PSORIATIC ARTHRITIS
EP4324326A1 (en) Mouse model for heart failure with preserved ejection fraction and method of obtaining this mouse model
Kapustnik et al. The use of telmisartan in the treatment of arterial hypertension with obesity
Cui et al. Effect of ritodrine on heart structure and function of pregnant women who after treatment for threat of preterm birth: A report based on echocardiographic assessment.
Akpınar et al. A Stroke Case Associated with Tibolone Intake in a Male-to-Female Transgender Patient: A Case Report and Review of Literature
Swierkot et al. AB0411 TNF alpha inhibitors influence the cardiovascular risk in rheumatoid arthritis patients
Kamakura et al. Comparative evaluation of the echocardiographic parameters of dogs with chronic mitral valve regurgitation treated with amlodipine or pimobendan
CN116850170A (zh) 加巴喷丁在制备用于治疗心肌梗死后心力衰竭的心房肥大或房颤的药物中的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23849301

Country of ref document: EP

Kind code of ref document: A1