CN111450095A - 一种n-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用 - Google Patents
一种n-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用 Download PDFInfo
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Abstract
本发明公开了一种N‑(噻唑‑2‑基)‑3‑(哌嗪‑1‑基)丙酰胺类化合物或其盐在药物制备中的应用,所述的化合物用于治疗或者预防慢性肾病,优选于高血糖或高血压引起的肾病,但不仅局限于这两种诱导物,具体的,该药物可以抑制或改善各种肾脏损伤。
Description
技术领域
本发明属于医药技术领域,具体涉及一种式(I)的化合物(代号LM8)或其药学上可接受的盐在制备用于治疗或预防慢性肾脏病药物中的用途。
背景技术
慢性肾病是高血糖或高血压等基础性疾病最常见的并发症之一。在这些风险因素的刺激下,肾小球基底膜变厚、肾小管间质扩展进行性纤维化。随着疾病的进展,最终发展为终末期肾病,严重影响患者的生活质量,甚至危及生命。
本发明人基于多年的药理与病理机制研究,发现了化合物LM8能够有效治疗高血糖、高血压等多因素诱发的慢性肾病,肾病相关的病理可以被显著改善。
发明内容
本发明的目的在于提供了N-(4-(3,4-二甲氧基苯基)噻唑-2-基)-3-(4-(3-硝基苄基)哌嗪-1-基)丙酰胺(式(I)的化合物,代号LM8)的新的用途。
具体而言,本发明提供了式(I)的化合物(LM8)或其药学上可接受的盐在制备用于治疗或预防慢性肾脏病的药物中的用途。
优选本发明的用途是在制备用于治疗或预防慢性肾脏病的药物中的用途。
本发明还提供了式(I)的化合物(LM8)或其药学上可接受的盐在制备用于改善慢性肾病的药物中的用途。
优选本发明的用途是在制备用于改善慢性肾病的药物用途。
肾病的发生有多种病因,包括泌尿系统阻塞、高血脂、高血压、自身免疫以及药物毒性反应等。不同的病因其治疗方式也有所不同,作为优选,本发明所针对的主要是糖尿病肾病或高血压性肾病,但不仅限于这两种致病因素;最优选,用于治疗肾脏损伤和肾脏组织功能改变。
优选在本发明的用途中,肾病的主要病理特征是是肾小球硬化、肾小管扩张。
所述的肾脏组织功能改变包括蛋白尿、肾功能降低、肾小管纤维化、基底膜增厚。
优选在本发明的用途中,式(I)的化合物(LM8)或其盐对血糖或血压的影响没有统计学意义。
本发明的用途中的药物含有有效剂量的式(I)的化合物(LM8)。有效剂量可以是单位给药剂量形式(如一片、一针、一丸或一剂)的药物中的含量,也可以是所需治疗/预防的患者的单位剂量(如单位体重剂量)。在本发明中,有效剂量(以含量计)可以是10μg-1g,优选是0.1mg-500mg,更优选是1mg-100mg。
本发明的用途中的药物通常还含有药学上可接受的载体。使用的药学上可接受的载体指无毒的填充剂、稳定剂、稀释剂、佐剂或其他制剂辅料。例如,稀释剂、赋形剂,如水、生理盐水等;填充剂,如淀粉、蔗糖等;粘合剂,如纤维素衍生物、藻酸盐、明胶和/或聚乙烯吡咯烷酮;湿润剂,如甘油;崩解剂,如琼脂、碳酸钙和/或碳酸氢钠;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇;吸附载体,如高岭土和/或皂粘土;润滑剂,如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外,本发明的药物组合物还可以进一步含有其它辅料,如香味剂、甜味剂等。根据本领域的公知技术,可以根据治疗目的、给药途径的需要将药物组合物制成各种剂型,优选该组合物为单位给药剂量形式,如冻干剂、片剂、胶囊、粉剂、乳液剂、水针剂或喷雾剂,更优选该药物组合物为注射剂型(如,冻干粉针剂)或口服剂型(如,片剂、胶囊)。药物可以通过常规途径施用,特别是肠内,例如口服,例如以片剂或胶囊剂形式,或非肠道施用,例如以可注射溶液剂或混悬剂形式,局部施用,例如以洗剂或凝胶剂,或以鼻剂或检剂形式。
以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是,这些描述仅仅是部分示例性的描述,并不构成对本发明范围的限制。依据本说明书的论述,本发明的许多变化、改变对所属领域技术人员来说都是显而易见了。
附图说明:
图1为式(I)的化合物(LM8)对糖尿病鼠血糖和体重的影响以及对模型尿蛋白和肾功能的改善作用。
图2为式(I)的化合物(LM8)对糖尿病小鼠肾脏纤维化的抑制效果。
图3为式(I)的化合物(LM8)对高浓度葡萄糖引起的体外肾小管上皮细胞纤维化的抑制效果。
图4为式(I)的化合物(LM8)对AngII引起的高血压肾小球纤维化、肿大的治疗作用。
具体实施方式:
本发明在以下的实施例中进一步说明。这些实施例只是为了说明本发明的目的,而不是用来限制本发明的范围。
实施例1本发明的化合物不影响小鼠的血糖与体重。
C57BL/6小鼠随机分为4组(每组8只),分别为:
对照组(Control组):健康C57BL/6小鼠;
1型糖尿病模型鼠(T1DM):利用链脲佐菌素(STZ)构建1型糖尿病老鼠模型;
化合物治疗组(STZ+LM8-5mg/kg):1型糖尿病模型鼠构建完成后,在第9周开始用5mg/kg的剂量隔天给鼠灌胃给药式(I)的化合物(LM8),1%CMC-Na悬液,连续给药8周。
化合物治疗组(T1DM+LM8-10mg/kg):1型糖尿病模型鼠构建完成后,在第9周开始用10mg/kg的剂量隔天给鼠灌胃给药式(I)的化合物(LM8),1%CMC-Na悬液,连续给药8周。
造模后的16周期间,每周记录各组鼠的血糖(Blood glucose)和体重(Bodyweight)。结果如图1A所示,应用高低两个剂量的化合物(LM8)并不影响糖尿病小鼠模型的体重。同时,治疗组小鼠血糖水平与T1DM组小鼠的血糖水平没有差异。
给药周期结束后处死小鼠,分别称取小鼠的肾脏重量,与体重作比并作图。结果显示高血糖引起的肾脏组织重量比增加可以被LM8显著降低,见图1C。同时,收取尿液样本,采用生化分析,检测尿蛋白与尿肌酐。图1D-E显示,式(I)的化合物(LM8)显著性缓解高糖引起的尿蛋白与肾功能低下。
实施例2本发明的化合物可明显抑制高血糖引起的肾脏纤维化
动物分组按照实施例1进行,在给药8周后,处死小鼠并获取肾脏组织。利用蛋白质免疫印迹法检测胶原蛋白IV(COL-IV)和纤维化标志物TGF-β的蛋白表达。图2A显示,T1DM组小鼠的肾组织中COL-IV和TGF-β的表达显著增加,而给予高低剂量的LM8均可明显抑制这些蛋白的表达。
将肾脏组织破碎提取RNA后,利用实时定量PCR法分别检测纤维化相关标志物COL-IV和TGF-β的基因表达。结果如图2B-C所示,LM8显著性抑制高血糖引起的肾脏组织中COL-IV和TGF-β的表达。
以4%福尔马林液固定、石蜡包埋、切片5μm厚度后进行苏木素&伊红(H&E)染色、天狼星红(Sirus Red)染色和Masson染色并镜检。图2D显示,高血糖引起肾小球肥大、肾小球基底膜变厚、肾小管扩张;同时,引起肾小管间质纤维化,但采用LM8治疗后能够显著缓解肾小管-肾小球的病理特征。
实施例3本发明的化合物明显改善高血糖引起的体外肾小管上皮细胞的纤维化。
利用高浓度的葡萄糖(HG,33mM)刺激肾小管上皮细胞NRK-52E 24小时后,裂解细胞,获得细胞总蛋白并利用蛋白免疫印迹法检测纤维化相关蛋白COL-IV和TGF-β的表达,以GAPDH作为内参。结果如图3A所示,HG诱导引起的COL-IV和TGF-β表达增加可明显的被LM8剂量依赖性的抑制。另外,利用HG刺激NRK-52E细胞8小时,利用TRIzol试剂提取细胞总RNA,应用实时定量PCR的方法检测COL-IV和TGF-β的RNA表达水平。结果见图3B-C,LM8在体外亦可剂量依赖性地显著抑制HG诱导引起的纤维化相关指标的RNA水平增加。
实施例4本发明的化合物不影响小鼠血压但明显改善高血压引起的肾小球纤维化
C57BL/6小鼠分为4组,每组8只,分别为:
空白对照组(Ctrl):健康鼠;
肾性高血压模型组(Ang II):利用Ang II皮下微泵注射(1000ng/kg/min)的方法造模,连续注射4周;
化合物治疗组(Ang II+LM8-5mg/kg):利用Ang II皮下微泵注射(1000ng/kg/min)2周;第17天以5mg/kg/day的剂量给鼠灌胃给药式(I)的化合物,连续2周
化合物治疗组(Ang II+LM8-10mg/kg):利用Ang II皮下微泵注射(1000ng/kg/min)2周;第17天以10mg/kg/day的剂量给鼠灌胃给药式(I)的化合物,连续2周。
图4A显示,皮下微泵注射Ang II后小鼠的血压显著升高,而治疗组小鼠的血压与Ang II相比,没有明显差异,表明式(I)所示化合物不影响模型小鼠的血压,其药理作用是不通过降压而实现。在处死小鼠前24h收集小鼠尿液,采用生化试剂盒检测发现给药后能够剂量依赖性的抑制模型组小鼠尿蛋白的增加(图4B)以及逆转尿液中肌酐的下降(图4C)。处死小鼠,取肾脏组织,以4%福尔马林液固定、石蜡包埋、切片5μm厚度后进行苏木素&伊红(H&E)染色和天狼星红(Sirus Red)染色并镜检。图4D显示,AngII引起肾小球肥大、肾小管扩张;同时,引起肾小管间质纤维化,而LM8治疗后病理特征得到明显改善。
Claims (9)
2.根据权利要求1所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的与肾脏有关的疾病由高血糖或者高血压引起。
3.根据权利要求2所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的与肾脏有关的疾病为高血糖引起的肾脏组织功能改变和病理损伤。
4.根据权利要求3所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的肾脏组织功能改变包括蛋白尿、肾功能降低、肾小管纤维化、基底膜增厚。
5.根据权利要求2所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的与肾脏有关的疾病为高血压引起的肾脏组织功能降低和肾脏病变。
6.根据权利要求5所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的肾脏病变的症状包括肾小球和肾小管硬化、肿大。
7.根据权利要求5所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的肾脏组织功能改变包括蛋白尿的增加、尿液中肌酐的下降和肾小管间质纤维化。
8.根据权利要求1所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的所述的药物用于抑制胶原蛋白IV和纤维化标志物TGF-β的蛋白表达。
9.根据权利要求1所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其盐在药物制备中的应用,其特征在于,所述的药物包含含有有效剂量的式(I)的化合物和药学上可接受的载体。
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