CN110496124A - 治疗脉管畸形的化合物 - Google Patents

治疗脉管畸形的化合物 Download PDF

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CN110496124A
CN110496124A CN201910705697.5A CN201910705697A CN110496124A CN 110496124 A CN110496124 A CN 110496124A CN 201910705697 A CN201910705697 A CN 201910705697A CN 110496124 A CN110496124 A CN 110496124A
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vascular
vascular malformation
ddx24
cysltr1
malformation
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单鸿
庞鹏飞
毛军杰
胡晓俊
何欢欢
肖非
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Fifth Affiliated Hospital of Sun Yat Sen University
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Abstract

本发明公开了治疗脉管畸形的化合物。发明人研究发现，CysLTR1拮抗剂可以上调血管平滑肌细胞DDX24中的表达，对脉管畸形具有一定的治疗或改善效果。

Description

治疗脉管畸形的化合物
技术领域
本发明涉及化合物的新应用及疾病的治疗方法，特别涉及治疗脉管畸形的化合物及方法。
背景技术
脉管系统主要由血管和淋巴管组成，承担人体重要的生理功能。脉管疾病是指各种因素所导致的脉管系统异常增生、沟通或形态改变。脉管疾病可发生于人体任何组织和部位，经常表现出侵袭性，甚至恶性生长的特性，对健康危害极大。发生于四肢、体表或颜面部的脉管疾病除影响美观外，还可形成边界不规则的占位，压迫或侵犯邻近的组织和器官，严重者导致正常生理功能的丧失。高流速型脉管疾病因血流动力学的紊乱可导致心功能衰竭。部分脉管疾病因管壁结构组织的异常极易发生出血，严重的内脏出血或颅内出血均可危及患者生命。
脉管疾病往往为先天性的，文献报道脉管疾病在人群中的发生率约为1.5％，其中2/3主要累及静脉。浅表部位的脉管疾病由于易于发现，患者往往能够得到早期诊断和治疗，临床疗效尚可。而深部组织的病变则有赖于影像学检查，如超声、CT、MRI、数字减影血管造影DSA等，在临床诊疗中经常漏诊，甚至误诊。患者经常是等到发生了严重的并发症时才得到诊治，错过了早期治疗时机，预后往往不良。目前，针对脉管疾病的治疗手段主要有手术切除、同位素疗法、激光疗法、介入栓塞及硬化治疗等。然而，以上治疗手段均属于对症治疗，都不能从病因上对脉管性疾病进行根治。
发明人在经过四年前期研究的基础上发现了一个遗传性脉管疾病家系，其病因不清，临床主要表现累及门静脉、肝静脉、肺动脉瓣、淋巴管系统；通过临床诊断及查阅文献，明确该家系所患疾病为一个全新的综合征，并命名为多器官静脉-淋巴管畸形综合征；通过基因筛查，确定DDX24基因突变为该综合征的致病基因；通过细胞实验、斑马鱼敲除实验证实DDX24是脉管发育的重要基因；同时在主要以肝静脉狭窄为临床特征的151例先天性脉管散发病例中，26例患者存在DDX24基因突变；验证DDX24突变是脉管性疾病的重要致病因素。前期研究表明DDX24基因突变是脉管畸形的重要致病基因(Pang P,Hu X,Zhou B,etal.DDX 24 Mutations Associated with Malformations of Major Vessels to theViscera[J].Hepatology,2018.)。
CN108018296A公开了DDX24基因突变及其应用，DDX24基因SNP突变，包括Glu271Lys、Lys11Glu、Arg436His。DDX24的突变Glu271Lys、Lys11Glu或Arg436His与脉管的发育有着显著的关联性。通过干扰DDX24，可以促进细胞迁移和脉管形成，导致脉管畸形的发生。通过检测DDX24的SNP位点，可以有效地预测人体的脉管畸形发生情况，可以用于遗传缺陷的筛查，同时有助于正确判断脉管异常疾病的类型，减少误诊，方便针对性治疗。
然而，现有技术中并没有有效治疗脉管畸形的方法。
半胱氨酰白三烯(The cysteinyl leukotrienes，CysLTs)是脂质类炎症介质，通过与受体CysLTR1或CysLTR2结合发挥作用，其中CysLTR1为对经典受体拮抗剂敏感的受体。CysLTR1正常情况下主要表达于外周血白细胞和支气管平滑肌细胞，炎症环境可上调病变部位CysLTR1表达，介导炎症病灶急性期组织损伤和慢性期组织增生性改变，并参与动脉粥样硬化、动脉瘤、肝硬化门静脉高压等慢性疾病的发生发展。因为肿瘤组织同样提供了炎性环境，可导致肿瘤组织中CysLTR1表达上调，与肿瘤转化密切相关。目前CysLTR1的主要拮抗剂为孟鲁司特钠(商品名：顺尔宁)。其他的CysLTR1拮抗剂包括Zafirlukast(DB00549)、Cinalukast(DB00587)、Nedocromil(DB00716)、Pranlukast(DB01411)，参见https://www.drugbank.ca。
发明内容
本发明的目的在于提供一种有效治疗或缓解脉管畸形的方法。
本发明所采取的技术方案是：
CysLTR1拮抗剂在制备治疗脉管畸形药物中的应用。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
一种治疗脉管畸形的方法，包括给予病人有效治疗量的CysLTR1拮抗剂。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
作为治疗脉管畸形药物的CysLTR1拮抗剂。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
本发明的有益效果是：
发明人研究发现，CysLTR1拮抗剂，如孟鲁司特钠可以上调血管平滑肌细胞DDX24中的表达，对脉管畸形具有一定的治疗或改善效果。
附图说明
图1是CysLTR1拮抗剂对人淋巴管内皮细胞生长的影响；
图2是人淋巴内皮细胞中DDX24的mRNA的qPCR实验结果；
图3是人脐静脉内皮细胞中DDX24的mRNA的qPCR实验结果；
图4是孟鲁司特钠对DDX24蛋白表达影响的实验结果；
图5是不同CysLTR1拮抗剂对DDX24的ATPase酶活性的影响；
图6是不同治疗方案对内脏脉管畸形患者的治疗效果CT图。
具体实施方式
CysLTR1拮抗剂在制备治疗脉管畸形药物中的应用。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
一种治疗脉管畸形的方法，包括给予病人有效治疗量的CysLTR1拮抗剂。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
作为治疗脉管畸形药物的CysLTR1拮抗剂。
在一些实例中，脉管畸形为DDX24异常表达引起的脉管畸形。
在一些实例中，脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
在一些实例中，CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
孟鲁司特钠药学上可接受的衍生物，特别包括其原研专利US4918081权利要求所请求保护的化合物。
下面结合实验，进一步说明本发明的技术方案。
CysLTR1拮抗剂对人淋巴管内皮细胞生长的影响
发明人在前期的实验过程，将孟鲁司特钠添加人淋巴管内皮细胞中，通过细胞活性实验发现，孟鲁司特钠抑制人淋巴管内皮细胞的生长，其半数抑制浓度约为36.9μM。实验结果如图1所示。
CysLTR1拮抗剂对DDX24表达的影响
发明人在前期的实验过程，将孟鲁司特钠添加血管内皮细胞中，通过RT-PCR检测发现，孟鲁司特钠可以上调脐静脉内皮细胞及人淋巴管内皮细胞中DDX24的表达(与对照比较<0.05)。实验结果如图2和图3所示。
其中：
图2为人淋巴内皮细胞中DDX24的mRNA的qPCR实验结果，图中，Con为阴性对照，MS为顺尔宁。*代表p<0.05。从图中可以看出，顺尔宁可以提高人淋巴内皮细胞中DDX24的mRNA水平。
图3为人脐静脉内皮细胞中DDX24的mRNA的qPCR实验结果，图中，Con为阴性对照，MS为顺尔宁。*代表p<0.05，***代表p<0.001。
在过表达DDX24荧光素酶报告基因中，加入顺尔宁孵育24h后检测DDX24蛋白的表达情况。结果如图4所示，图中，Con为阴性对照，MS为顺尔宁，MS-10指作用浓度为10μM，MS-20指作用浓度为20μM。从图中可以看出，顺尔宁能够促进DDX24蛋白的表达。
CysLTR1拮抗剂对DDX24的ATPase酶活性的影响
发明人将孟鲁司特钠及其同类化合物普仑司特、扎鲁司特添加血管内皮细胞中，通过ATPase活性检测实验显示孟鲁司特钠及其同类化合物普仑司特、扎鲁司特抑制DDX24的ATPase酶活性。实验结果如图5所示，图中，Con为阴性对照，MS为顺尔宁，Pra为普仑司特，Zaf为扎鲁斯特。结果显示孟鲁司特钠及其同类化合物对DDX24的ATPase酶活性有微弱的抑制作用
CysLTR1拮抗剂孟鲁司特钠明显改善脉管血管畸形患者的临床症状
孟鲁司特钠明显改善家族性内脏血管畸形患者的临床症状
发明人将本院收治的内脏脉管畸形患者(属于脉管畸形)随机予以2名患者孟鲁司特钠口服治疗，实验结果如图6所示。其中2名患者CT示胸腹水明显吸收，左右叶肝脏比例无明显异常，下肢水肿、气促明显缓解；1名患者近期孟鲁司特钠治疗后，患者腹胀、气促等症状明显缓解。

Claims (4)

1.CysLTR1拮抗剂在制备治疗脉管畸形药物中的应用。
2.根据权利要求1所述的应用，其特征在于：脉管畸形为DDX24异常表达引起的脉管畸形。
3.根据权利要求2所述的应用，其特征在于：脉管畸形包括门静脉狭窄、肝静脉狭窄、肺动脉瓣狭窄、乳糜胸、门脉高压、MOVLD综合征、特发性非硬化性门脉高压征。
4.根据权利要求1～3任一项所述的应用，其特征在于：CysLTR1拮抗剂选自孟鲁司特钠、Zafirlukast、Cinalukast、Nedocromil、Pranlukast及其药学上可接受的衍生物。
CN201910705697.5A 2019-04-10 2019-08-01 治疗脉管畸形的化合物 Pending CN110496124A (zh)

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CN115245575A (zh) * 2022-06-14 2022-10-28 中山大学附属第五医院 血管平滑肌细胞特异性ddx24及其下游分子在血管发育中的应用
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