CN115778961A - Pd173074在制备抗瘙痒药物中的应用 - Google Patents
Pd173074在制备抗瘙痒药物中的应用 Download PDFInfo
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Abstract
本发明提供了PD173074在制备抗瘙痒药物中的应用，属于医药技术领域。本发明首次提出PD173074具有抑制瘙痒的作用，可以有效抑制手术切口痒模型和博来霉素诱发痒模型中小鼠的瘙痒行为。本发明还提供了一种抗瘙痒药物，所述药物的活性成分包括PD173074，所述药物能够有效抑制瘙痒。
Description
技术领域
本发明属于医药技术领域，尤其涉及PD173074在制备抗瘙痒药物中的应用。
背景技术
瘙痒(itch或pruritus)是引起搔抓欲望的不愉快的感觉体验，其发生与神经***、内分泌***、免疫***密切相关。正常状态下的瘙痒是机体对皮肤刺激产生的保护性反应，然而，长期瘙痒可以引起睡眠剥夺、焦虑、抑郁等问题，严重影响生活质量。瘙痒可以单独出现(例如多见于老年人的皮肤瘙痒症，其特征为以瘙痒为主，无明显原发性损害)，也可以是其他疾病的伴随症状。现有研究表明：表皮或真皮内多种细胞参与瘙痒发生，如角质形成细胞、T和B淋巴细胞、肥大细胞、嗜碱性粒细胞、嗜酸性粒细胞和成纤维细胞等产生大量与瘙痒相关的细胞因子和炎症介质，如IL-4、IL-6、IL-17、IL-22、IL-31、IL-33、半胱氨酸和丝氨酸蛋白酶、神经生长因子、神经肽、P物质、降钙素相关基因肽、内皮素、5-羟色胺、白三烯、***素等，这些分子作为切口痒机制研究和干预治疗的潜在靶点。目前认为瘙痒发生主要涉及组胺依赖信号通路和非组胺依赖信号通路，然而，现有的抗组胺类药物对于慢性瘙痒疗效差、副作用较多。因此，非组胺依赖瘙痒抑制剂的作用值得关注。
成纤维细胞因子FGF包括旁分泌和内分泌两种类型，前者结合肝素硫酸蛋白多糖(heparin-sulfate proteoglycans)，后者结合Klotho家族跨膜蛋白，二者均可以作用于成纤维细胞因子受体FGFR。FGFR包括FGFR1、FGFR2、FGFR3和FGFR4等亚型，是受体酪氨酸激酶(RTKs)超家族成员，可以通过FRS2a和PLC途径，激活RAS-ERK、PI3K-AKT、DAG-PKC信号通路，参与正常细胞增殖、分化、上皮间质转化等过程。此外，FGF和FGFR也可以作为致癌基因，驱动肿瘤细胞增殖，参与多种类型肿瘤的发生，是抗肿瘤药物研发的热点靶点。近年来，FGF及其受体FGFR介导的细胞内信号通路在炎症免疫、组织损伤修复中的作用正越来越多的关注。
化合物N-[2-[4-(二乙氨基)丁基]氨基-6-(3,5-二甲氧基苯基)吡啶并[2,3-D-7-嘧啶基]-N'-(1,1-二甲基)脲(以下简称PD173074)是一种ATP竞争性FGFR1抑制剂，剂量依赖性地抑制FGFR1磷酸化，IC50在1～5nM范围内。体外细胞实验表明：PD173074抑制神经突生长，拮抗少突胶质细胞的增殖和分化反应。小鼠体内实验显示：PD173074对新血管形成具有抑制作用，显著延缓肿瘤生长。然而，FGFR1拮抗剂PD173074能否用于瘙痒的治疗尚无明确报道。
发明内容
有鉴于此，本发明的目的在于提供PD173074在制备抗瘙痒药物中的应用。
为了实现上述发明目的，本发明提供了以下技术方案：
本发明提供了PD173074在制备抗瘙痒药物中的应用。
优选的，所述瘙痒包括手术切口导致的瘙痒。
优选的，所述瘙痒包括博来霉素诱发的瘙痒。
优选的，所述PD173074的有效剂量为10μg/kg～100mg/kg。
本发明还提供了一种抗瘙痒药物，所述药物的活性成分包括PD173074。
优选的，所述药物包括注射制剂、乳剂、软膏剂。
优选的，所述药物中PD173074的含量为0.1～99wt％。
优选的，所述药物还包括药物学上可接受的载体。。
本发明的有益效果：
本发明首次提出PD173074在制备抗瘙痒药物中的应用。本发明通过构建手术切口痒模型和博来霉素诱发痒模型，发现PD173074可以有效抑制两种模型中小鼠瘙痒行为，表明PD173074具有抑制瘙痒作用。
附图说明
图1为不同实验组对小鼠手术切口痒行为抑制效果；
图2为不同实验组对BLM诱发的瘙痒行为抑制效果。
具体实施方式
本发明提供了PD173074在制备抗瘙痒药物中的应用。
本发明所述PD173074是FGFR1的ATP竞争性抑制剂，本发明对于PD173074的具体来源没有特殊限定，采用本领域常规市售产品均可。
在本发明中，所述瘙痒类型包括手术切口导致的瘙痒，还包括博来霉素诱发的瘙痒。本发明通过对手术切口痒模型或博来霉素诱发痒模型的小鼠进行腹腔注射，发现PD173074可以有效抑制两种模型中小鼠瘙痒行为。
本发明所述PD173074的有效剂量为10μg/kg～100mg/kg，优选为100μg/kg～50mg/kg。
本发明还提供了一种抗瘙痒药物，所述药物的活性成分包括PD173074。本发明所述抗瘙痒药物中活性成分可以以PD173074作为唯一活性成分，也可以将PD173074与其他具有抑制瘙痒作用的活性成分联合使用。
本发明所述药物包括但不限于注射制剂、乳剂、软膏剂。本发明所述药物还包括药物学上可接受的载体。本发明对于药物中所含有的其他辅料成分没有特殊限定，采用本领域药物常用辅料即可。
本发明所述药物中PD173074的含量为0.1～99.9wt％，优选为10～80wt％，更优选为17～73wt％。
下面结合实施例对本发明提供的技术方案进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
下述实施例中，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
本实施例提供PD173074对手术切口痒的抑制作用。
将C57小鼠(体重20～30g)用4％异氟烷麻醉，用无菌手术刀片在右侧脸部做一长度0.5厘米的切口(Incision)，6小时后测量瘙痒行为。瘙痒行为测量具体操作如下：将切口处理的小鼠放入透明塑料行为学鼠盒中，用高清摄像机记录小鼠搔抓次数，录制过程保持室内安静，搔抓次数计数方法从后肢抬起接触到瘙痒部位开始，到后肢放回到地面或口中为止，整个过程计算一次发作，计数30分钟内的搔抓次数。每组均为腹腔注射10分钟后开始记录，每组小鼠6只。
实验1：
对照组为Incision+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
实验组为Incision+PD173074(1mg/kg，HY-10321，MCE公司，溶于0.9％生理盐水，体积20μl)。
实验2：
对照组为Incision+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
阳性药物1组为Incision+Bilastine(5mg/kg，HY-14447，MCE公司，溶于0.9％生理盐水，体积20μl).
实验3：
对照组为Incision+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
阳性药物2组为Incision+PD176252(5mg/kg，204067-01-6，TOCRIS公司，溶于0.9％生理盐水，体积20μl)。
结果见表1和图1。
表1不同实验组对小鼠手术切口痒行为抑制效果
由表1和图1可知，与对照组相比，PD173074显著抑制手术切口痒行为，抑制率为65％(图1A)。阳性药物1(抑制组胺依赖性痒的化合物：组胺H1受体拮抗剂Bilastine)显著抑制手术切口痒行为，抑制率为55％(图1B)；阳性药物2(抑制非组胺依赖性痒的化合物：蛙皮素受体拮抗剂PD176252)不能显著抑制手术切口痒行为，抑制率为35％(图1C)。表明，本发明所述PD173074对手术切口痒的抑制效果明显，抑制率高于现有阳性药物。
实施例2
本实施例提供PD173074对博来霉素诱发痒的抑制作用。
C57小鼠(体重20～30g)用4％异氟烷麻醉，在右侧脸部皮下注射博来霉素(Bleomycin，简称BLM，50μg/20μl，HY-17565A，MCE公司)，隔日1次，连续处理5周，测量瘙痒行为。瘙痒行为测量具体操作如下：将小鼠放入透明塑料行为学鼠盒中，用高清摄像机记录小鼠搔抓次数，录制过程保持室内安静，搔抓次数计数方法从后肢抬起接触到瘙痒部位开始，到后肢放回到地面或口中为止，整个过程计算一次发作，计数30分钟内的搔抓次数。每组均为腹腔注射10分钟后开始记录，每组小鼠6只。
实验1：
对照组为BLM+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
实验组为BLM+PD173074(1mg/kg，HY-10321，MCE公司，溶于0.9％生理盐水，体积20μl)。
实验2：
对照组为BLM+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
阳性药物1组为BLM+Bilastine(5mg/kg，HY-14447，MCE公司，溶于0.9％生理盐水，体积20μl).
实验3：
对照组为BLM+Vehicle(Vehicle为0.9％生理盐水，体积20μl)；
阳性药物2组为BLM+PD176252(5mg/kg，204067-01-6，TOCRIS公司，溶于0.9％生理盐水，体积20μl)。
结果见表2和图2。
表2不同实验组对BLM诱发的瘙痒行为抑制效果
由表2和图2可知，与对照组相比，PD173074显著抑制BLM诱发的瘙痒行为，抑制率为77％(图2A)。阳性药物1(抑制组胺依赖性痒的化合物：组胺H1受体拮抗剂Bilastine)显著抑制BLM诱发的瘙痒行为，抑制率为56％(图2B)；阳性药物2(抑制非组胺依赖性痒的化合物：蛙皮素受体拮抗剂PD176252)显著抑制BLM诱发的瘙痒行为，抑制率为56％(图2C)。表明，本发明所述PD173074对BLM诱发的瘙痒行为抑制效果明显，高于现有阳性药物。
以上所述仅是本发明的优选实施方式，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，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.PD173074在制备抗瘙痒药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述瘙痒包括手术切口导致的瘙痒。
3.根据权利要求1所述的应用，其特征在于，所述瘙痒包括博来霉素诱发的瘙痒。
4.根据权利要求1所述的应用，其特征在于，所述PD173074的有效剂量为10μg/kg～100mg/kg。
5.一种抗瘙痒药物，其特征在于，所述药物的活性成分包括PD173074。
6.根据权利要求5所述的药物，其特征在于，所述药物包括注射制剂、乳剂、软膏剂。
7.根据权利要求5或6所述的药物，其特征在于，所述药物中PD173074的含量为0.1～99wt％。
8.根据权利要求5或6所述的药物，其特征在于，所述药物还包括药物学上可接受的载体。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103757026A (zh) * | 2013-12-20 | 2014-04-30 | 广州圣露生物技术有限公司 | FGFR2b胞外段的基因序列、多肽及其应用 |
| WO2015107171A1 (en) * | 2014-01-17 | 2015-07-23 | Sanofi | Methods of identifying patients suffering from liver cancer who will most likely benefit from a treatment with an antagonist anti-fgfr4 antibody |
| CN108341837A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其在医学上的用途 |
| CN108341815A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103757026A (zh) * | 2013-12-20 | 2014-04-30 | 广州圣露生物技术有限公司 | FGFR2b胞外段的基因序列、多肽及其应用 |
| WO2015107171A1 (en) * | 2014-01-17 | 2015-07-23 | Sanofi | Methods of identifying patients suffering from liver cancer who will most likely benefit from a treatment with an antagonist anti-fgfr4 antibody |
| CN108341837A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其在医学上的用途 |
| CN108341815A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其用途 |
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