WO2024207142A1 - 化合物2-溴十六烷酸在治疗脑血管疾病中的应用 - Google Patents

化合物2-溴十六烷酸在治疗脑血管疾病中的应用 Download PDF

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WO2024207142A1
WO2024207142A1 PCT/CN2023/085926 CN2023085926W WO2024207142A1 WO 2024207142 A1 WO2024207142 A1 WO 2024207142A1 CN 2023085926 W CN2023085926 W CN 2023085926W WO 2024207142 A1 WO2024207142 A1 WO 2024207142A1
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compound
drug
cerebrovascular diseases
bromohexadecanoic acid
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French (fr)
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张慧灵
马玉琪
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Suzhou University
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Suzhou University
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    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to drug application technology, and specifically relates to application of the compound 2-bromohexadecanoic acid in treating cerebrovascular diseases.
  • Stroke is a group of diseases with symptoms of brain tissue ischemia and hemorrhagic injury as the main clinical manifestations, also known as cerebral infarction or cerebrovascular accident.
  • the disease has an acute onset, extremely high disability and mortality rates, and is the second leading cause of death in the world today. It is becoming more and more serious with the aging of the population.
  • Acute ischemic stroke acute cerebral infarction
  • the pathogenesis of ischemic stroke is complex, involving multiple mechanisms such as peroxidation, energy metabolism disorders, calcium overload, and excitatory amino acid toxicity.
  • tissue plasminogen activator t-PA
  • intravenous injection tissue plasminogen activator
  • t-PA tissue plasminogen activator
  • 2-Bromopalmitate (2-BP) can reverse the dynamic imbalance of mitochondrial fusion and fission in spinal cord astrocytes to relieve bone cancer pain and inhibit T cell activation, making it a potential immunosuppressant for the treatment of autoimmune diseases.
  • 2-BP has a protective effect in cerebrovascular diseases such as ischemic stroke.
  • the invention discloses application of a compound 2-bromohexadecanoic acid in preparing a medicine for treating cerebrovascular diseases.
  • 2-BP can significantly reduce the volume of acute cerebral infarction in mice with focal cerebral ischemia, significantly improve their neurological symptoms, inhibit reactive astrocyte proliferation, and has a protective effect on brain nerves, indicating that 2-BP can be used to treat ischemic stroke. Therefore, the present invention discloses the use of the compound 2-bromohexadecanoic acid in the preparation of drugs for reducing cerebral infarction volume, improving cerebral ischemic neurological symptoms, inhibiting reactive astrocyte proliferation, and treating ischemic stroke.
  • the present invention discloses for the first time that 2-BP can significantly reduce the acute cerebral infarction volume of focal ischemic stroke mice, significantly improve their neurobehavioral symptoms, inhibit reactive astrocyte proliferation, and has a brain neuroprotective effect.
  • 2-BP can be used as a promising drug for treating cerebrovascular diseases.
  • FIG1 is a schematic diagram showing the effect of compound 2-BP on reducing the volume of cerebral infarction in the acute phase of cerebral ischemia in mice.
  • FIG2 is a schematic diagram showing the effect of compound 2-BP on improving neurological symptoms in mice with cerebral ischemia.
  • FIG3 is a schematic diagram showing the effect of compound 2-BP on palmitoyl transferase ZDHHC5 and reactive astrocyte GFAP.
  • FIG4 is a schematic diagram showing the protective effect of compound 2-BP on oxygen-glucose deprivation and reoxygenation astrocytes.
  • FIG5 is a schematic diagram showing the effect of compound 2-BP on inhibiting reactive astrocyte proliferation.
  • the present invention discloses that 2-BP has the effect of treating ischemic stroke, and provides new targets, new action mechanisms and new ideas for the drug development of cerebrovascular diseases such as ischemic stroke.
  • the raw materials used in the present invention are existing products, and the specific experimental operations and tests are conventional techniques.
  • mice Male C57 mice were randomly divided into a normal control group (sham), a model group (I/R), and a drug-treated group (I/R+2-BP), with 10 mice in each group.
  • the transient middle cerebral artery occlusion (tMCAO) model of mice was established by conventional suture method. Reperfusion was performed after 60 min of ischemia, and 2-BP (40 mg/kg) was immediately injected into the tail vein during reperfusion. The mice were decapitated and the brains were removed and sliced for TTC staining to observe the effect of 2-BP on the volume of cerebral infarction in the acute phase of cerebral ischemia. Before killing the mice, the Longa method was used to score the neurological symptoms of the mice after reperfusion (I/R) in the acute phase of cerebral ischemia. The higher the score, the more obvious the neurological deficit. The neurological symptom scoring criteria are shown in Table 1.
  • compound 2-BP can reduce the neurological symptom scores of mice with cerebral ischemia.
  • compound 2-BP can reduce the volume of cerebral infarction in mice during the acute phase of cerebral ischemia.
  • Figure 4 is a schematic diagram of the protective effect of compound 2-BP on oxygen-glucose deprivation and reoxygenation astrocytes; compared with the model group, **p ⁇ 0.01. As shown in Figure 4, compound 2-BP improves cell viability in a dose-dependent manner.
  • Figure 5 is a schematic diagram of the effect of compound 2-BP on inhibiting reactive astrocyte proliferation. As shown in Figure 5, compound 2-BP can inhibit reactive astrocyte proliferation.
  • the present invention discloses for the first time that 2-BP can significantly reduce the volume of acute cerebral infarction in mice with focal cerebral ischemia, significantly improve their neurological symptoms, inhibit reactive astrocyte proliferation, and has a neuroprotective effect. This indicates that 2-BP can be used as a promising drug for treating cerebrovascular diseases such as ischemic stroke.

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  • Medicinal Chemistry (AREA)
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Abstract

公开了化合物2-溴十六烷酸在治疗脑血管疾病中的应用，2-BP能明显减少局灶性缺血性脑卒中小鼠急性期脑梗死体积、显著改善其神经行为学症状、抑制反应性星形胶质细胞增生，具有脑神经保护作用。

Description

化合物2-溴十六烷酸在治疗脑血管疾病中的应用 技术领域
本发明属于药物应用技术，具体涉及化合物2-溴十六烷酸在治疗脑血管疾病中的应用。
 背景技术
脑卒中是一组以脑组织缺血及出血性损伤症状为主要临床表现的疾病，又称脑中风或脑血管意外。该病发病急，有极高的致残率和致死率，是当今世界导致死亡的第二大病因，且随着人口老龄化变得越来越严重。急性缺血性脑卒中（急性脑梗死）是最常见的卒中类型，缺血性脑卒中的发病机制复杂，涉及过氧化、能量代谢障碍、钙超载、兴奋性氨基酸毒性等多种机制。目前唯一被美国FDA批准用于缺血性脑卒中治疗的药物是组织型纤维酶原激活剂（tissue plasminogen activator, t-PA，静脉注射），它可以溶解血栓，使血管再通，从而恢复血流。但由于组织型纤维酶原激活剂( t-PA)的治疗窗较窄（卒中后4.5小时使用有效）及易引起出血，仅有小部分患者得到溶栓治疗。因此，寻找治疗缺血性脑卒中新的靶点，具有新作用机制、不良反应少的药物是一件急需解决的问题。
 技术问题
2-溴十六烷酸（2-Bromopalmitate ，2-BP)可以逆转脊髓星形胶质细胞线粒体融合和裂变动态失衡来减轻骨癌症疼痛，可以抑制T细胞活化，使其成为治疗自身免疫性疾病的潜在免疫抑制剂。但2-BP是否在缺血性脑卒中等脑血管疾病中具有保护作用尚未见文献报道。
 技术解决方案
本发明公开了化合物2-溴十六烷酸在制备治疗脑血管疾病药物中的应用。
2-BP能明显减少局灶性脑缺血小鼠急性期脑梗死体积、显著改善其神经症状、抑制反应性星形胶质细胞增生，具有脑神经保护作用，说明2-BP可以用于治疗缺血性脑卒中。因此，本发明公开了化合物2-溴十六烷酸在制备减少脑梗死体积药物、改善脑缺血神经症状药物、抑制反应性星形胶质细胞增生药物、治疗缺血性脑卒中药物中的应用。
 有益效果
本发明首次公开了2-BP能明显减少局灶性缺血性脑卒中小鼠急性期脑梗死体积、显著改善其神经行为学症状、抑制反应性星形胶质细胞增生，具有脑神经保护作用。2-BP可以作为一种有前景的治疗脑血管疾病的药物。
 附图说明
图1为化合物2-BP对于减少脑缺血小鼠急性期的脑梗死体积的影响示意图。
图2为化合物2-BP对改善脑缺血小鼠的神经症状的影响示意图。
图3为化合物2-BP对棕榈酰化转移酶ZDHHC5和反应性星形胶质细胞GFAP的影响示意图。
图4为化合物2-BP对于氧糖剥夺再复氧星形胶质细胞保护作用示意图。
图5为化合物2-BP对于抑制反应性星形胶质细胞增生示意图。
 本发明的实施方式
本发明公开了2-BP具有治疗缺血性脑卒中的作用，为缺血性脑卒中等脑血管疾病的药物研发提供新靶点、新作用机制及新思路。本发明采用的原料为现有产品，具体实验操作以及测试为常规技术。
实施例一
雄性C57小鼠，随机分为正常对照组（sham）、模型组（I/R）、给药组(I/R+2-BP)，每组10只。采用常规线栓法制作小鼠短暂性大脑中动脉闭塞模型（tMCAO）。缺血60 min后再灌注，再灌注时立即尾静脉注射2-BP（40mg/kg）。将小鼠断头取脑并切片TTC染色观察2-BP对脑缺血急性期脑梗死体积的影响。在处死小鼠前采用Longa法对再灌注后（I/R）的小鼠进行脑缺血急性期的神经症状评分，评分越高，神经功能缺陷越明显。如表1所示为神经症状评分标准。
图1为化合物2-BP对改善脑缺血小鼠的神经症状的影响示意图；mean±SD，n=10；与模型组比较，***p<0.001。由图2可知：化合物2-BP能够减少脑缺血小鼠的神经症状评分。
图2为化合物2-BP对于减少脑缺血小鼠急性期的脑梗死体积的影响示意图；mean±SD，n=10；与模型组比较，****p<0.0001。由图1可知：化合物2-BP能够减少脑缺血小鼠急性期的脑梗死体积。
图3为化合物2-BP对反应性星形胶质细胞GFAP的影响示意图；mean ± SD，n=5；与模型组比较，**p<0.01，****p<0.0001。由图3可知：化合物2-BP能够抑制反应性星形胶质细胞GFAP的表达。
图4为化合物2-BP对于氧糖剥夺再复氧星形胶质细胞保护作用示意图；与模型组比较，**p<0.01。由图4可知：化合物2-BP以剂量依赖的方式改善细胞活力。
图5为化合物2-BP对于抑制反应性星形胶质细胞增生示意图。由图5可知：化合物2-BP能够抑制反应性星形胶质细胞增生。
以上结果表明：2-BP对缺血性脑损伤具有一定的保护作用，可以用于这一类脑血管疾病的预防和治疗。
本发明首次公开了2-BP能明显减少局灶性脑缺血小鼠急性期脑梗死体积、显著改善其神经症状、抑制反应性星形胶质细胞增生，具有脑神经保护作用。说明2-BP可以作为一种有前景的治疗缺血性脑卒中等脑血管疾病的药物。

Claims (10)

  1. 化合物2-溴十六烷酸在制备治疗脑血管疾病药物中的应用。
  2.  化合物2-溴十六烷酸在制备减少脑梗死体积药物中的应用。
  3.  化合物2-溴十六烷酸在制备改善脑缺血神经症状药物中的应用。
  4.  化合物2-溴十六烷酸在制备抑制反应性星形胶质细胞增生药物中的应用。
  5.  化合物2-溴十六烷酸在制备治疗缺血性脑卒中药物中的应用。
  6. 根据权利要求1至5任意一项所述的应用，其特征在于，药物的活性成分为2-溴十六烷酸。
  7. 根据权利要求1至5任意一项所述的应用，其特征在于，药物为注射药物或者口服药物。
  8.  一种治疗脑血管疾病的药物，其特征在于，活性成分为2-溴十六烷酸。
  9.  根据权利要求8所述治疗脑血管疾病的药物，其特征在于，药物为注射药物或者口服药物。
  10.  根据权利要求8所述治疗脑血管疾病的药物，其特征在于，脑血管疾病包括缺血性脑卒中。
PCT/CN2023/085926 2023-04-03 2023-04-03 化合物2-溴十六烷酸在治疗脑血管疾病中的应用 Ceased WO2024207142A1 (zh)

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