CN113209084A - 化合物cp0119在制备用于治疗炎性肠病的药物中的应用 - Google Patents
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Abstract
Description
技术领域
本发明涉及药物化学领域,具体地,涉及一种化合物CP0119在制备用于治疗炎性肠病的药物中的应用。
背景技术
炎症性肠病(inflammatorybowel disease,IBD)是一种以慢性炎性反应和胃肠道上皮损伤为特征的自身免疫性肠道疾病,表现为缓解与复发交替的肠道炎症,它主要包括溃疡性结肠炎(Ulcerative colitis,UC)和克罗恩氏病(Crohn’s Disease,CD),发病原因与环境、遗传、肠道微生物、免疫功能紊乱等有关。目前关于该病发病机制的基本共识是:易感个体在环境因素作用下,肠黏膜屏障削弱,肠道致病菌群及其有害成分穿过黏膜屏障,引发局部炎症反应。该病易反复,治疗花费大,且目前尚无彻底根治的方法,对社会和家庭造成了极大经济负担。
目前尚无彻底治愈IBD的药物上市,主要的治疗策略还是单抗药物缓解IBD症状,但该类药物均需注射给药,患者顺应性差,治疗成本高,长期使用易产生耐药性及不良反应,因此,针对IBD的药物已成为近年来该领域的研究热点,阐明其发生发展机制,探索新的潜在的药物靶点,开发出针对IBD的疗效确认、相对安全、价格合理的药物具有重要的社会意义和医学意义。
阿奇霉素可与胃肠道内的胃动素受体发生相互作用、加速胃肠蠕动、改善肠道免疫力,基于此研究,以大环内酯类为前体药物,对其进行结构改造,最终得到了抗抗炎性肠病候选药物CP0119。CP0119具有药效显著、安全性可靠、市场价格低等优势,且化合物工艺稳定、重现性好、收率高,纯度高达99%,具有较高的成药性。
发明内容
针对以上问题,本发明提供了一种化合物CP0119在制备用于治疗炎性肠病的药物中的应用,其中,所述化合物CP0119的结构如下式(I)所示:
本发明还提供了一种用于治疗炎性肠病的药物,包括:化合物CP0119或在药学上可接受的盐、酯、水合物以及辅料。
优选的,用于治疗炎性肠病的药物中化合物CP0119的有效剂量为10mg/kg~100mg/kg。
优选的,在以上药物中,所述化合物CP0119在药学上可接受的盐为有机盐或无机盐。
优选的,在以上药物中,所述有机盐为甲磺酸盐、甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、对甲基苯磺酸盐、萘磺酸盐、乳酸盐和苯甲酸盐中的一种或几种;
优选的,在以上药物中,所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐和磷酸盐中的一种或几种。
优选的,在以上药物中,所述药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂或它们的组合。
优选的,在以上药物中,所述药物的给药方式包括口服、注射、植入、外用、喷雾、吸入或它们的组合。
本发明的研究表明,化合物CP0119对炎性肠病有良好的功效,无不良反应,可减缓葡聚糖硫酸钠盐诱导的小鼠炎性肠病,在治疗、缓解或改善炎性肠病方面具有良好的应用前景。
附图说明
图1为各组小鼠的体重变化;
图2为各组小鼠的疾病活动指数(DAI)评分;
图3为各组小鼠结直肠长度的对比。(*,P<0.05,即统计学上具有显著性差异);
图4为各组小鼠炎性肠病病理切片;
图5为各组小鼠occludin蛋白免疫组化结果图;
图6为各组小鼠claudin-1蛋白免疫组化结果图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应该理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。
本发明提供了一种化合物CP0119在制备用于治疗炎性肠病的药物中的应用,其中,化合物CP0119的结构如下式(I)所示:
实施例1
化合物CP0119对葡聚糖硫酸钠盐诱导的小鼠炎性肠病模型的影响
炎性肠病动物模型制备:SPF级C57 BL/6小鼠60只,雄性,20g±2g,饲养于南开大学动物房。随机将60只小鼠分为6组,每组10只,采用3%DSS诱导IBD模型;在适应喂养阶段,使小鼠自由进食和饮水,适应三天后,将饮用水换成3%(W/V)的DSS溶液(空白组除外),给小鼠自由饮用。每只小鼠每天的饮水量按6mL计算,次日补充DSS溶液至日饮水量,DSS溶液共给予7天,第8天将DSS溶液换回饮用水,给药组开始给药,空白组和模型组给生理盐水,共给药7天。
分组情况:
(1)空白组:每天灌胃给予0.1ml/10g生理盐水;
(2)模型组:每天灌胃给予0.1ml/10g生理盐水;
(3)阳性药组:确定柳氮磺胺吡啶给药量为200mg/kg,每天给予0.1ml/10g柳氮磺胺吡啶混悬液(20mg/mL);
(4)CP0119低剂量组:确定给药量为10mg/kg,每天灌胃给予0.1ml/10g CP0119溶液(1mg/mL);
(5)CP0119中剂量组:确定给药量为50mg/kg,每天灌胃给予0.1ml/10g CP0119溶液(5mg/mL);
(6)CP0119高剂量组:确定给药量为100mg/kg,每天灌胃给予0.1ml/10g CP0119溶液(10mg/mL)。
体重的测量:每天固定选择上午9点钟记录各组每日小鼠体重,绘制体重变化表格(表1)。
表1各组小鼠的体重变化表格(g)
疾病活动情况的评分:从造模开始至给药结束,观察各组小鼠体重变化、粪便性状、便血情况,参考文献中的评分标准进行评分,每日将各指标评分相加,作为DAI(表3)。评分标准如下(表2):
表2疾病活动情况的评分标准
评分 | 体重下降(%) | 粪便性状 |
0 | 无 | 正常 |
1 | 1~5 | 轻度松软 |
2 | 6~10 | 松软 |
3 | 11~15 | 腹泻 |
4 | >15 | 血便 |
表3各组小鼠DAI
结直肠长度的测量:给予DSS 7天后(第8天),对小鼠进行灌胃给药,给药7天后(第15天)将小鼠处死,暴露小鼠腹腔,用镊子找出小鼠盲肠部位(呈弯曲状,较粗),剥离其余组织,沿着结肠连着直肠部位,从肛门部位底部剪下(标号例如1、2、3、4、5),将肠子按标号摆到纸上,用直尺测量每只鼠的盲肠结、直肠长度并记录(表4),拍照保存。
表4各组小鼠结直肠长度(cm)
对肠组织切片进行病理染色:将肠子的盲肠部位剪下,用针头吸取适量PBS,插入结、直肠中,将其中的粪便和血块冲洗干净,用剪刀剪取结肠部位0.5cm,并固定于甲醛中,将保存在甲醛中的结肠进行常规脱水、石蜡包埋、切片、苏木素-伊红(HE)染色、中性树胶封片处理后,应用正置显微镜采集染色图像数据。
对肠组织切片进行免疫组化染色分析:将包埋好的结肠组织切片进行脱蜡处理后经过抗原修复等,分别与occludin蛋白和claudin-1蛋白一抗过夜,孵二抗,进行DAB显色,经过二甲苯透明后用中性树胶封片处理,应用正置显微镜采集染色图像数据。
实验结果如图1至图6所示,图1为各组小鼠体重,由图可知与空白组相比,各造模组体重均有明显下降,在给药后,柳氮磺胺吡啶阳性药组、CP0119低、中、高剂量组小鼠体重均有上升,且CP0119低、中、高剂量组呈现量效关系;由图2可知,与空白组相比,各造模组DAI均有明显上升,在给药后,柳氮磺胺吡啶阳性药组、CP0119低、中、高剂量组小鼠DAI均有下降,且CP0119低、中、高剂量组呈现量效关系;由图3可知,与空白组相比,模型组小鼠结直肠长度显著缩短(P<0.05),表明DSS模型造模成功且模型稳定,与模型组相比,柳氮磺胺吡啶阳性药组小鼠结直肠长度显著增长(P<0.05)、CP0119低剂量组小鼠小鼠结直肠长度显著增长(P<0.05)、CP0119中剂量组小鼠小鼠结直肠长度显著增长(P<0.01)、CP0119高剂量组小鼠小鼠结直肠长度显著增长(P<0.01),并且CP0119中、高剂量组小鼠结直肠长度增长程度均优于柳氮磺胺吡啶阳性药组,且CP0119低、中、高剂量组呈现量效关系;由图4可知,HE染色观察CP0119组小鼠炎症程度明显低于模型组小鼠,CP0119治疗组的小鼠急性溃疡性结肠炎程度低于模型组小鼠,表明CP0119可有效减缓葡聚糖硫酸钠盐诱导的小鼠炎性肠病;由图5和图6occludin、claudin-1蛋白免疫组化结果图可知CP0119组小鼠两种蛋白表达含量明显高于模型组小鼠,且低、中、高剂量组的occludin蛋白和claudin-1蛋白表达量在逐渐升高,表明CP0119可有效减缓葡聚糖硫酸钠盐诱导的小鼠炎性肠病。
综上,CP0119对炎性肠病有具良好的功效,无不良反应,可减缓葡聚糖硫酸钠盐诱导的小鼠炎性肠病,在治疗、缓解或改善炎性肠病方面具有良好的应用前景。
以上仅为本发明的具体实施方式,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、改进等,均应包含在本发明的保护范围之内。
Claims (8)
2.一种用于治疗炎性肠病的药物,其特征在于:包括化合物CP0119或其在药学上可接受的盐、酯、水合物以及辅料。
3.根据权利要求2所述的药物,其特征在于:所述药物中化合物CP0119的有效剂量为10mg/kg~100mg/kg。
4.根据权利要求3所述的药物,其特征在于:所述化合物CP0119在药学上可接受的盐为有机盐或无机盐。
5.根据权利要求4所述的药物,其特征在于:所述有机盐为甲磺酸盐、甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、对甲基苯磺酸盐、萘磺酸盐、乳酸盐和苯甲酸盐中的一种或几种的混合。
6.根据权利要求4所述的药物,其特征在于:所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐和磷酸盐中的一种或几种的混合。
7.根据权利要求3所述的药物,其特征在于:所述药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂或它们的组合。
8.根据权利要求3所述的药物,其特征在于:所述药物的给药方式包括口服、注射、植入、外用、喷雾、吸入或它们的组合。
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