WO2022252391A1 - 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用 - Google Patents

吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用 Download PDF

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WO2022252391A1
WO2022252391A1 PCT/CN2021/111475 CN2021111475W WO2022252391A1 WO 2022252391 A1 WO2022252391 A1 WO 2022252391A1 CN 2021111475 W CN2021111475 W CN 2021111475W WO 2022252391 A1 WO2022252391 A1 WO 2022252391A1
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p2y6r
inflammation
atherosclerosis
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李环球
朱一凡
宋佳滔
刘莉
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苏州大学
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  • the invention relates to the technical field of medicinal chemistry, in particular to the application of a pyrazole derivative in the preparation of P2Y6R-related drugs for treating atherosclerosis and anti-inflammation.
  • P2 receptors The receptors of nucleotides outside the cell have been identified and classified as purinergic receptors, and purinergic receptors are divided into two categories: P1 and P2 receptors, of which P2 receptors are further divided into ligand-gated ion channel receptors ( P2XR) and G protein-coupled receptors (P2YR).
  • P2XR ligand-gated ion channel receptors
  • P2YR G protein-coupled receptors
  • P2 receptors and their extracellular nucleotides widely regulate the body's immune response and inflammation, and have become drug targets that many well-known international pharmaceutical companies pay attention to.
  • P2Y 2 R agonist Diquafosol P2Y 12 R antagonist clopidogrel
  • P2X 7 R selective antagonist AZD9056 have been marketed or are in the clinical stage.
  • clopidogrel is one of the antiplatelet drugs widely used clinically and has been used alone or in combination to treat atherosclerosis.
  • the application of clopidogrel in atherosclerosis is still to reduce the risk of myocardial infarction in patients with atherosclerosis from the perspective of antithrombotic, and there is no clear connection with the occurrence of atherosclerosis.
  • P2Y 6 R is a member of eight subtypes of the P2Y receptor family (P2Y 1 R, P2Y 2 R, P2Y 4 R, P2Y 6 R, P2Y 11 R, P2Y 12 R, P2Y 13 R and P2Y 14 R), Expressed in various organs and tissues such as immune organs, cardiovascular system, and nervous tissue, the endogenous ligand of P2Y 6 receptor is an extracellular nucleotide molecule, which specifically activates phospholipase C through its selective agonist UDP (PLC), up-regulate the concentration of intracellular Ca 2+ to achieve the purpose of transmitting intercellular signals and regulating various physiological functions of cells.
  • PLC selective agonist UDP
  • P2Y 6 R when stimulated, it can promote the recruitment and chemotaxis of neutrophils and macrophages, and release a variety of inflammatory cytokines, chemokines and mast cell mediators. Studies on P2Y 6 R gene knockout mouse models have shown that P2Y 6 R is involved in the occurrence and development of diseases such as cardiovascular disease, respiratory inflammation, and gastrointestinal inflammation.
  • P2Y 6 R mediates the activity of extracellular nucleotides to participate in the occurrence and development of cardiovascular diseases, which is reflected in the promotion of vascular inflammation, the enhancement of vascular tone, and the promotion of smooth muscle cell contraction and proliferation.
  • the response of vascular endothelial cells, macrophages and vascular smooth muscle cells to UDP was significantly weakened, and these types of cells happened to be the core cells in the process of atherosclerosis.
  • the deletion of the P2Y 6 R gene can inhibit atherosclerosis and plaque inflammation in mice induced by a high-cholesterol diet. Therefore, the development of antagonists targeting the P2Y 6 receptor can achieve anti-inflammatory effects by interfering with the body's innate immunity , which has good innovation and application prospects in the field of drug development for the treatment of inflammation such as atherosclerosis.
  • the technical problem to be solved by the present invention is to provide an application of a pyrazole derivative in the preparation of P2Y 6 R-related drugs for treating atherosclerosis and anti-inflammation.
  • the present invention provides the application of pyrazole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating atherosclerosis and anti-inflammation, wherein the chemical structure of pyrazole derivatives is as follows:
  • the atherosclerosis is P2Y 6 R-related atherosclerosis.
  • the present invention provides the use of pyrazole derivatives or pharmaceutically acceptable salts thereof in the preparation of P2Y 6 R antagonists, wherein the chemical structure of the pyrazole derivatives is as follows:
  • the biological activity of the above-mentioned small molecular compound is determined, and it is found that it has obvious antagonistic activity to P2Y 6 R, and can significantly reduce PLC ⁇ , NLRP3, ASC, and Caspase-1 in THP-1 cells induced by ox-LDL and the expressions of IL-1 ⁇ and IL-18 inflammatory factors in the cell culture supernatant.
  • the above-mentioned pharmaceutically acceptable salt is selected from hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, toluenesulfonate, fumarate and tartaric acid One or more of salt.
  • the present invention provides the application of pyrazole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating atherosclerosis and anti-inflammation.
  • the present invention discovers for the first time that pyrazole derivatives have the function of P2Y6R antagonists, have obvious antagonism on P2Y6R -related inflammation, and can be used to prepare P2Y6R -related anti-inflammatory drugs.
  • Figure 1 is a histological section diagram of compounds improving pathological histomorphological changes of AS mice aorta;
  • Figure 2 is a Western Blot diagram of the effect of compounds on the expression of pyroptosis-related proteins in THP-1 cells stimulated by ox-LDL;
  • Figure 3 is the co-localization immunofluorescence blot and flow cytometry diagram of the NLRP3-ASC inflammasome under the stimulation of ox-LDL stimulation by the compound;
  • Figure 4 is a histogram of the number of Caspase-1 positive cells and the number of Caspase-1 and PI double positive cells under the stimulation of compounds inhibiting ox-LDL.
  • the previously constructed human P2Y 6 R stably transfected HEK293 cells were cultured in DMEM medium (containing 10% fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin), and inoculated into 6-well culture plates before the experiment.
  • the cell is 5 ⁇ 10 5 cells/ml, and the cells are cultured at 37° C., 95% O 2 , and 5% CO 2 humidity.
  • the serum-free medium was starved for 12 hours, and 1 ⁇ M compound was added to each well. After 30 minutes of reaction, 10 ⁇ M UDP was added to incubate for 12 hours, and samples were collected to detect the content of intracellular inositol 3-phosphate (IP3).
  • IP3 intracellular inositol 3-phosphate
  • IP3 enzyme-linked immunosorbent assay kit adopts competition ELISA method.
  • the IP3 antigen is coated on the microtiter plate, and the IP3 in the sample or standard competes with the coated IP3 for the binding site on the biotin-labeled anti-IP3 monoclonal antibody during the experiment, and the free components are washed away.
  • Add horseradish peroxidase-labeled avidin, biotin and avidin specifically combine to form immune complexes, and free components are washed away.
  • Chromogenic substrate (TMB) is added, and TMB turns blue under the catalysis of horseradish peroxidase, and turns yellow after adding stop solution.
  • High-fat diet was used to establish the AS model of LDLR -/- mice, and 20 mg/kg compound was used for intervention treatment.
  • the results show that the compound can effectively inhibit the abnormal changes of TC, TG, LDL-C and HDL-C in AS blood lipid levels caused by HFD; at the same time, the compound can effectively improve the increase of lipid deposition in the main plaque of the mouse, thickening of the arterial wall, Pathological changes such as narrow lumen, high collagen fiber content, and intimal fibrosis (Figure 1), prove that P2Y 6 R antagonists have good therapeutic effects in mouse AS models, and demonstrate their potential as therapeutic drugs for AS .
  • the ox-LDL-induced THP-1 cell model was used to intervene with the compound to detect the relevant indicators of pyroptosis.
  • the test results showed that human THP-1 cells could significantly increase the protein expression of PLC ⁇ , NLRP3, ASC, Caspase-1 in the cells and IL-1 ⁇ , IL-18 in the cell culture supernatant after stimulation with ox-LDL Significantly increased, the corresponding protein expression decreased after adding the compound ( Figure 2).
  • the results of immunofluorescence detection showed that the compound could reverse the up-regulation of NLRP3-ASC inflammasome caused by ox-LDL ( Figure 3).

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Abstract

本发明提供了吡唑衍生物或其可药用的盐在制备治疗动脉粥样硬化及抗炎药物中的应用。本发明首次发现了吡唑衍生物具备P2Y 6R拮抗剂的功能，对P2Y 6R相关炎症具有明显的拮抗作用，可以用作制备P2Y 6R相关的抗炎药物。 (I)

Description

吡唑衍生物在制备P2Y6R相关治疗动脉粥样硬化及抗炎药物中的应用
本申请要求于2021年06月01日提交中国专利局、申请号为202110609149.X、发明名称为“吡唑衍生物在制备P2Y6R相关治疗动脉粥样硬化及抗炎药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学技术领域，尤其涉及一种吡唑衍生物在制备P2Y6R相关治疗动脉粥样硬化及抗炎药物中的应用。
背景技术
核苷酸在细胞外的受体被确认并分类为嘌呤能受体，嘌呤受体分为P1和P2受体两大类，其中P2受体又分为配体门控离子通道型受体(P2XR)和G蛋白偶联型受体(P2YR)。P2受体及其胞外核苷酸广泛调控了机体的免疫应答及炎症发生过程，成为国际多个知名制药公司关注的药物靶点。目前已有P2Y 2R激动剂地夸磷索(Diquafosol)、P2Y 12R拮抗剂氯吡格雷、P2X 7R的选择性拮抗剂AZD9056多个靶向P2受体的药物上市或处于临床阶段。值得注意的是，氯吡格雷是目前临床广泛使用的抗血小板药物之一，已被用于单独或联合使用治疗动脉粥样硬化。然而，氯吡格雷在动脉粥样硬化方面的应用仍然是从抗血栓的角度，降低动脉粥样硬化患者心肌梗死风险，与动脉粥样硬化的发生并没有明确联系。
P2Y 6R是P2Y受体家族八个亚型(P2Y 1R，P2Y 2R，P2Y 4R，P2Y 6R，P2Y 11R，P2Y 12R，P2Y 13R和P2Y 14R)中的一员，在免疫器官、心血管系统、神经组织等多种器官和组织中表达，P2Y 6受体的内源性配体是胞外核苷酸分子，通过其选择性激动剂UDP特异性激活磷脂酶C(PLC)，上调细胞内Ca 2+浓度，达到传递细胞间信号、调节细胞各种生理功能的目的。目前研究表明，当P2Y 6R受到激动时，可促进中性粒细胞和巨噬细胞的募集和趋化，并释放多种炎症细胞因子、趋化因子和肥大细胞介质。对P2Y 6R的基因敲除的小鼠模型的研究表明，P2Y 6R参与心血管疾病、呼吸道炎症及胃肠道炎症等疾病的发生发展。
P2Y 6R介导细胞外核苷酸的活动参与心血管疾病的发生发展，体现在促进血管炎症反应、增强血管张力、促进平滑肌细胞的收缩与增殖等方面。P2Y 6R 基因敲除的小鼠模型中，血管内皮细胞、巨噬细胞和血管平滑肌细胞对UDP的响应显著减弱，而这几类细胞恰好是动脉粥样硬化病程中的核心细胞。近期Blood上报道了P2Y 6R基因的缺失能够抑制高胆固醇饮食诱导的小鼠动脉粥样硬化和斑块炎症，因此，针对P2Y 6受体开发拮抗剂可通过干预机体固有免疫而达到抗炎效果，在动脉粥样硬化等炎症治疗药物开发领域很好的创新性和应用前景。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种吡唑衍生物在制备P2Y 6R相关治疗动脉粥样硬化及抗炎药物中的应用。
本发明提供了吡唑衍生物或其可药用的盐在制备治疗动脉粥样硬化及抗炎药物中的应用，其中吡唑衍生物的化学结构如下所示：
Figure PCTCN2021111475-appb-000001
本发明优选的，所述动脉粥样硬化为P2Y 6R相关动脉粥样硬化。
另一方面，本发明提供了吡唑衍生物或其可药用的盐在制备P2Y 6R拮抗剂的应用，其中吡唑衍生物的化学结构如下所示：
Figure PCTCN2021111475-appb-000002
本发明对上述小分子化合物进行了生物学活性测定，发现它对P2Y 6R具有明显的拮抗活性，且能明显降低ox-LDL诱导的THP-1细胞中PLC β、NLRP3、 ASC、Caspase-1和细胞培养上清液中IL-1β、IL-18炎症因子的表达。
上述可药用的盐选自盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐和酒石酸盐中的一种或多种。
与现有技术相比，本发明提供了吡唑衍生物或其可药用的盐在制备治疗动脉粥样硬化及抗炎药物中的应用。本发明首次发现了吡唑衍生物具备P2Y 6R拮抗剂的功能，对P2Y 6R相关炎症具有明显的拮抗作用，可以用作制备P2Y 6R相关的抗炎药物。
附图说明
图1为化合物改善AS小鼠主动脉病理组织形态学改变组织切片图；
图2为化合物对ox-LDL刺激下THP-1细胞中焦亡相关蛋白表达影响Western Blot图；
图3为化合物抑制ox-LDL刺激下NLRP3-ASC炎症小体的共定位免疫荧光印记与流式细胞检测图；
图4为化合物抑制ox-LDL刺激下Caspase-1阳性细胞数和Caspase-1、PI双阳性细胞数柱状图。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的吡唑衍生物(以下图中编号为C3)在制备P2Y 6R相关治疗动脉粥样硬化及抗炎药物中的应用进行详细描述。
实施例1
化合物对P2Y 6受体体外拮抗活性测试
将前期构建的人P2Y 6R稳转HEK293细胞培养于DMEM培养基中(含10％胎牛血清、100U/ml青霉素和100μg/ml链霉素)，实验前接种至6孔培养板，接种密度为5×10 5cells/ml，细胞于37℃、95％O 2、5％CO 2湿度条件下培养。实验前换无血清培养基饥饿12h，每孔加入1μM化合物，反应30min后加入10μM UDP孵育12h后收集样品检测胞内3磷酸肌醇(IP3)含量。
3磷酸肌醇(IP3)酶联免疫吸附测定试剂盒采用竞争ELISA法。用IP3抗原包被于酶标板上，实验时样品或标准品中的IP3与包被的IP3竞争生物素标记 的抗IP3单抗上的结合位点，游离的成分被洗去。加入辣根过氧化物酶标记的亲和素，生物素与亲和素特异性结合而形成免疫复合物，游离的成分被洗去。加入显色底物(TMB)，TMB在辣根过氧化物酶的催化下呈现蓝色，加终止液后变成黄色。用酶标仪在450nm波长处测OD值，IP3浓度与OD450值之间呈反比，通过绘制标准曲线计算出样品中IP3的浓度。最后计算每组复孔的平均OD值。以浓度为横坐标，OD值为纵坐标，在双对数坐标纸上绘出四参数逻辑函数的标准曲线；通过标准曲线计算出样品中IP3的浓度。实验重复三次，取平均值并计算化合物对P2Y 6R的IC 50和SD。
实验结果如表1所示：
表1化合物对P2Y 6受体体外拮抗活性测试结果
Figure PCTCN2021111475-appb-000003
实施例2
化合物在小鼠的动脉粥样硬化模型中的药效学研究
采用高脂饲料(HFD)建立LDLR -/-小鼠AS模型，并用20mg/kg的化合物进行干预治疗。结果表明，化合物能够有效地抑制HFD导致的AS血脂水平TC、TG、LDL-C和HDL-C的异常改变；同时化合物能有效改善小鼠主斑块的脂质沉积增加、动脉壁增厚、管腔狭窄、胶原纤维含量高、内膜纤维化等病理性改变(图1)，证明P2Y 6R拮抗剂在小鼠AS模型中有很好的治疗效果，展现了其作为AS治疗药物的潜力。
实施例3
化合物在ox-LDL诱导的巨噬细胞中的体外抗炎活性研究
为了测试化合物抗炎活性，采用ox-LDL诱导的THP-1细胞模型，加入化合物干预治疗，检测细胞焦亡的相关指标。检测结果显示，人THP-1细胞在 ox-LDL刺激后能够明显升高细胞中PLC β、NLRP3、ASC、Caspase-1和细胞培养上清液中IL-1β、IL-18炎症因子的蛋白表达显著增加，加入化合物后相应蛋白表达降低(图2)。免疫荧光检测结果显示：化合物能够逆转ox-LDL造成的NLRP3-ASC炎症小体的上调(图3)。流式检测结果显示：加入化合物的人THP-1细胞在ox-LDL诱导后细胞释放到上清液中的Caspase-1阳性细胞数和Caspase-1、PI双阳性细胞数较模型组均显著降低(图4)。上述结果表明，化合物通过抑制P2Y 6R调控的通路从而抑制巨噬细胞的焦亡和炎症因子表达。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (4)

  1. 吡唑衍生物或其可药用的盐在制备治疗动脉粥样硬化及抗炎药物中的应用，其中吡唑衍生物的化学结构如下所示：
    Figure PCTCN2021111475-appb-100001
  2. 根据权利要求1所述的应用，其特征在于，所述动脉粥样硬化为P2Y 6R相关动脉粥样硬化。
  3. 吡唑衍生物或其可药用的盐在制备P2Y 6R拮抗剂的应用，其中吡唑衍生物的化学结构如下所示：
    Figure PCTCN2021111475-appb-100002
  4. 根据权利要求1或3所述的应用，其特征在于，所述可药用的盐选自盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐和酒石酸盐中的一种或多种。
PCT/CN2021/111475 2021-06-01 2021-08-09 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用 WO2022252391A1 (zh)

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CN113274391B (zh) * 2021-06-01 2022-07-05 苏州大学 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用

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CN113274391A (zh) * 2021-06-01 2021-08-20 苏州大学 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用

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