CN110623955A - Wnk激酶抑制剂在预防和/或治疗高原病中的用途 - Google Patents
Wnk激酶抑制剂在预防和/或治疗高原病中的用途 Download PDFInfo
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- CN110623955A CN110623955A CN201910874577.8A CN201910874577A CN110623955A CN 110623955 A CN110623955 A CN 110623955A CN 201910874577 A CN201910874577 A CN 201910874577A CN 110623955 A CN110623955 A CN 110623955A
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Abstract
本发明公开了WNK激酶抑制剂在预防和/或治疗高原病中的用途，特别是WNK463在预防和/或治疗高原肺水肿、高原性心脏病中的用途。本申请的发明人经试验发现，WNK激酶抑制剂(特别是WNK463)对模拟高原环境(特别是海拔5500米的高原环境)大鼠的肺损伤显示出较好的保护作用，其具有开发成防治高原病(特别是高原肺水肿或高原性心脏病)的药物的潜在价值。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种WNK激酶抑制剂在制备预防和/或治疗高原病的产品中的用途，特别是WNK463在制备预防和/或治疗高原肺水肿、高原性心脏病的产品中的用途。
背景技术
高原系指海拔在3000m以上的地区，包括高山和高原。高原空气稀薄，大气压低，氧分分压低。易使人缺氧。对高原低氧环境不能适应而发生的疾病称高原病(mountainsickness)。我国是一个多山国家，有许多大山和高原，海拔3000m以上的地区占总面积的1/6。由平原移居或短期逗留高原的人均可发生高原病。该病一般分为急性和慢性两大类。急性高原病指初入高原时出现的急性缺氧反应或疾病，依其严重程度分为轻型(或良性)和重型(或恶性)。轻型即反应型或急性高原反应；重型又分为：脑型急性高原病(又称高原昏迷或高原脑水肿)、肺型急性高原病(又称高原肺水肿)、混合型(即肺型和脑型的综合表现)。慢性高原病指抵高原后半年以上方发病或原有急性高原病症状迁延不愈者，少数高原世居者也可发病，包括高原性心脏病、高原红细胞增多症、高原高血压、高原低血压或混合型疾病(本病指高原红细胞增多症、高原高血压及高原心脏病三型中，有两型同时存在者，称为混合型。最常见的是红细胞增多症合并心脏病和红细胞增多症合并高血压)。
近年随着高原医疗救护手段的提高，对这类疾病的防治取得了较大的进展，但真正有效的防护药物未获得国际社会的一致认同。因此，寻找发现新的防治药物成为高原医学研究工作的一项重要工作。
发明内容
为克服现有技术的不足，本发明提供一种WNK激酶抑制剂在制备预防和/或治疗高原病的产品中的用途。
具体地，上述WNK激酶抑制剂具有通式Ⅰ的结构：
其中，R1-R13独立地选自：氢、取代或未取代的烷基、取代的或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、-COR16、-C(O)OR16、-C(O)NR16R17、-CH＝NR16、-CN、-OR16、-OC(O)R16、-S(O)t-R16、-NR16R17、-NR16C(O)R17、-NO2、-N＝CR16R17和卤素；
R14和R15独立地选自：氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂环基、取代的或未取代的杂环基烷基、-COR16、-C(O)OR16和-C(O)NR16R17；或者，R14和R15与二者共同连接的氮原子形成取代或未取代的杂环基；
R16和R17独立地选自：氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的杂环基和卤素。
在本发明的一个实施方式中，R1、R2、R3、R12和R13独立地选自：氢、卤素和取代或未取代的烷基。
在本发明的一个实施例中，R1、R2、R3、R12和R13均为氢。
在本发明的一个实施方式中，R4、R5、R6、R7、R8、R9、R10和R11独立地选自：氢、卤素和取代或未取代的烷基。
在本发明的一个实施例中，R4、R5、R6、R7、R8、R9、R10和R11均为氢。
在本发明的一个实施例中，R14为氢。
在本发明的一个实施方式中，R15选自：氢、取代或未取代的烷基和取代的或未取代的环烷基。
在本发明的一个具体实施方式中，R15选自：C1-6的烷基，如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基等。
在本发明的一个实施例中，R15为叔丁基。
在本发明的一个实施方式中，上述WNK激酶抑制剂为WNK463，即N-(叔丁基)-1-(1-(5-(5-(三氟甲基)-1,3,4-恶二唑-2-基)吡啶-2-基)哌啶-4-基)-1H-咪唑-5-甲酰胺，其结构式如下：
具体地，本发明所述的高原病包括在高原环境下产生的急性高原病和慢性高原病。
具体地，上述高原环境为海拔2500m以上的高原环境，特别是海拔5500m以上的高原环境。
具体地，上述急性高原病包括：高原肺水肿、高原脑水肿、或脑、肺异常症状同时存在的混合型疾病。
具体地，上述慢性高原病包括：高原性心脏病、高原红细胞增多症、高原高血压、高原低血压或高原红细胞增多症、高原高血压及高原性心脏病三型中有两型同时存在混合型疾病。
在本发明的一个实施方式中，上述高原病为高原肺水肿。
在本发明的另一个实施方式中，上述高原病为高原性心脏病。
具体地，上述产品为药品、食品、保健品，等。
本发明还提供一种药物组合物在制备预防和/或治疗高原病的产品中的用途，该药物组合物包含WNK激酶抑制剂以及一种或多种药学上可接受的辅料。
具体地，上述用途中，WNK激酶抑制剂、高原病和产品具有本发明上述定义。
在本发明的一个实施方案中，上述药物组合物中，WNK激酶抑制剂为唯一活性成分。
在本发明的另一个实施方案中，上述药物组合物中，WNK激酶抑制剂与一种或多种其它用于预防和/或治疗高原病的活性成分联用，其中，WNK激酶抑制剂与该活性成分可配制用于同时、单独或顺序给药(simultaneous,separate or sequentialadministration)。
具体地，上述药物组合物的制剂形式可以是任何可药用的剂型，如，片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、液体、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如，口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如，皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如，直肠栓剂、阴道栓剂)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等、口服或胃肠外制剂。在本发明的一个实施方式中，上述药物组合物为口服制剂。
具体地，上述药物组合物通过口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、局部用药、非肠道给药，例如，皮下、静脉、肌内、鞘内、心室内、胸骨内、颅内或腹膜内注射或输入的途径向体内施加药物组合物，或借助外植储器用药。在本发明的一个实施方式中，上述药物组合物通过口服给药。
具体地，上述药学上可接受的辅料选自：溶剂、乳化剂、增塑剂、崩解剂、填充剂、粘合剂、甜味剂和润滑剂等中的一种或两种以上的组合。
具体地，上述溶剂如水、甲醇、乙醇、异丙醇、羟丙基-β-环糊精、聚乙二醇-15-羟基硬脂酸酯、二氯甲烷丙酮或乙酸乙酯中的一种或两种以上的组合。
具体地，上述乳化剂如聚乙二醇油酸酯、聚乙烯醇、甘油硬脂酸酯或吐温-80中的一种或两种以上的组合。
具体地，上述增塑剂如聚乙二醇、蓖麻油、甘油或山梨醇中的一种或两种以上的组合。
具体地，上述崩解剂如交联聚维酮、羟甲纤维素钠、甲基纤维素钠淀粉或低取代羟丙纤维素中的一种或两种以上的组合。
具体地，上述填充剂如微晶纤维素、赤藓醇、山梨醇、甘露醇、预胶化淀粉、碳酸钙、蔗糖或乳糖中的一种或两种以上的组合。
具体地，上述粘合剂如聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、明胶、瓜尔胶、羟甲基纤维素钠、羟丙甲纤维素、硅酸镁铝、乙基纤维素、羟乙基纤维素、预胶凝淀粉、阿拉伯胶、聚乙烯醇、聚维酮、麦芽糊精或海藻酸钠中的一种或两种以上的组合。
具体地，上述甜味剂如阿司帕坦、木糖醇、薄荷脑、薄荷香精、安塞蜜、甜菊糖苷或三氯蔗糖中的一种或两种以上的组合。
具体地，上述润滑剂如滑石粉、氢化硬脂酸钙、十二烷基硫酸镁、硬脂酰醇富马酸钠、水合硅胶钠、氢化蓖麻油、硬脂酸锌或硬脂酸镁中的一种或两种以上的组合。
本发明还提供一种预防和/或治疗高原病的方法，其包括向由此需要的受试者给与有效量的WNK激酶抑制剂或本发明上述药物组合物的步骤。
具体地，上述方法中，WNK激酶抑制剂、药物组合物、高原病具有本发明上述定义。
在本发明的一个实施方案中，上述受试者为哺乳动物，特别是人。
具体地，上述WNK激酶抑制剂的有效量取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断，等。
本申请的发明人经试验发现，WNK激酶抑制剂(特别是WNK463)对模拟高原环境(特别是海拔5500米的高原环境)大鼠的肺损伤显示出较好的保护作用，其具有开发成防治高原病(特别是高原肺水肿或高原性心脏病)的药物的潜在价值。
附图说明
图1所示为各组大鼠的mPAP的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
图2所示为各组大鼠的RVSP的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
图3所示为各组大鼠的PAAT的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
图4所示为各组大鼠的CO的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
图5所示为各组大鼠的IVSd的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
图6所示为各组大鼠的RVHI的变化，*p<0.05，**p<0.01，***p<0.001，模型组vs对照组；#p<0.05，##p<0.01，###p<0.001，治疗组vs模型组；one-way ANOVA。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1、材料与方法
1.1动物
SD大鼠36只(200g左右，雄性，清洁级)，购自北京维通利华实验动物有限公司，许可证号：SCXK(京)2016-0006。低压氧舱饲养，定时给予全价营养饲料喂食，室温22-25℃，湿度50％-70％。
1.2试剂与样品
WNK463粉剂，购买selleck；
DMSO，购自solaxbio；
PEG300，购自源叶生物；
吐温80，购自美仑生物。
WNK463的溶剂配制方法：5％DMSO+30％PEG300+5％吐温80+60％双蒸水，pH＝7。
1.3仪器
多因素复合环境模拟医学科学实验舱(型号DYC-3285，北京军事医学科学院仪器中心)；
小动物呼吸机(kent scientific，美国)；
多功能生理仪(Millar，美国)；
小动物超声仪(Visual Sonics Inc，加拿大)。
1.4实验设计与过程
将36只大鼠随机分为3组：对照组、模型组和治疗组，每组12只，其中，模型组和治疗组置于实验舱中，调节舱内压力至380mmHg，模拟海拔5500米的高原环境，每天打开实验舱1小时，以便给动物添加饲料和水及给予相应的药物处理，同时保持大鼠所处的环境12：12小时昼夜交替，21天后分别灌胃给予溶剂(模型组)或WNK463(3mg/kg)+溶剂(治疗组)，每日两次并持续14天。对照组大鼠放在同一房间中常压常氧环境下饲养。
1.5指标检测方法
3％的戊巴比妥钠，0.2ml/100g腹腔注射麻醉大鼠，行超声检测。之后将大鼠仰卧位固定于手术台上，气管切管，连接呼吸机，开胸，暴露心脏，导管插入右心室，行右心导管检查。处死大鼠，取出心脏，去除心房组织及附着脂肪，分离左右心室，滤纸吸干水分，分别称重。
1.6统计学方法
所有数据用Mean±SD表示，组间比较为单因素方差分析，p＜0.05为差异有统计学意义，采用GraphPad Prism 5软件包进行统计学处理。
2、实验结果
2.1各组处理对大鼠右心-肺循环压力的影响
各组大鼠的肺动脉平均压(mPAP)和右心室收缩压(RVSP)的变化分别如图1和图2所示。
由图1和图2可知，35天后，与对照组相比，模型组大鼠的mPAP和RVSP明显升高，差异具有显著性(p＜0.001)。与模型组相比，WNK463治疗组大鼠的mPAP和RVSP明显降低，差异有统计学意义(p＜0.001)。
2.2各组处理对大鼠右心-肺循环功能的影响
各组大鼠的肺动脉血流加速时间(PAAT)和CO变化分别如图3和图4所示。
由图3和图4可知，35天后，与对照组相比，模型组大鼠的PAAT和CO明显降低，差异具有显著性(p＜0.001和p＜0.01)。与模型组相比，WNK463治疗组大鼠的PAAT和CO明显升高，差异有统计学意义(p＜0.05和p＜0.001)。
2.3各组处理对大鼠右室肥厚的影响
各组大鼠的室间隔舒末厚度(IVSd)和右心室肥厚指数(RVHI)的变化分别如图5和图6所示。
由图5和图6可知，35天后，与对照组相比，模型组大鼠的IVSd和RVHI明显升高，差异具有显著性(p＜0.001)。与模型组相比，WNK463治疗组大鼠的IVSd和RVHI明显降低，差异有统计学意义(p＜0.001)。
上述结果表明，WNK463对模拟5500米高原环境大鼠的肺动脉高压、右心肥厚等具有保护作用，可被开发为保护对抗高原环境的药物。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种WNK激酶抑制剂或包含WNK激酶抑制剂的药物组合物在制备预防和/或治疗高原病的产品中的用途，其中，所述WNK激酶抑制剂具有通式Ⅰ的结构：
其中，R1-R13独立地选自：氢、取代或未取代的烷基、取代的或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、-COR16、-C(O)OR16、-C(O)NR16R17、-CH＝NR16、-CN、-OR16、-OC(O)R16、-S(O)t-R16、-NR16R17、-NR16C(O)R17、-NO2、-N＝CR16R17和卤素；
R14和R15独立地选自：氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂环基、取代的或未取代的杂环基烷基、-COR16、-C(O)OR16和-C(O)NR16R17；或者，R14和R15与二者共同连接的氮原子形成取代或未取代的杂环基；
R16和R17独立地选自：氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的烯基、取代或未取代的芳基、取代或未取代的杂环基和卤素；
所述药物组合物包含所述WNK激酶抑制剂以及一种或多种药学上可接受的辅料。
2.如权利要求1所述的用途，其特征在于，所述R1-R13独立地选自：氢、卤素和取代或未取代的烷基。
3.如权利要求1所述的用途，其特征在于，所述R14为氢，R15选自：氢、取代或未取代的烷基和取代的或未取代的环烷基。
4.如权利要求1所述的用途，其特征在于，所述R1-R14均为氢；和/或，所述R15为叔丁基。
5.如权利要求1所述的用途，其特征在于，所述WNK激酶抑制剂为WNK463，其结构式如下：
6.如权利要求1任一项所述的用途，其特征在于，所述高原病为高原肺水肿或高原性心脏病。
7.如权利要求1-6任一项所述的用途，其特征在于，所述药物组合物中，所述WNK激酶抑制剂为唯一活性成分。
8.如权利要求1-6任一项所述的用途，其特征在于，所述药物组合物中，所述WNK激酶抑制剂与一种或多种其它用于预防和/或治疗高原病的活性成分联用。
9.如权利要求1所述的用途，其特征在于，所述产品为药品、食品或保健品。
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| CN116076440B (zh) * | 2022-11-09 | 2023-09-26 | 河南省精神病医院(新乡医学院第二附属医院) | 验证wnk1抑制剂在制备治疗认知障碍药物中的应用 |
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