CN106074597A - 硝普钠作为吲哚胺2,3-双加氧酶-1抑制剂的用途 - Google Patents
硝普钠作为吲哚胺2,3-双加氧酶-1抑制剂的用途 Download PDFInfo
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- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 title claims abstract description 17
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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Abstract
本发明通过硝普钠或其药学上可接受的盐作为吲哚胺2,3‑双加氧酶‑1抑制剂（IDO1）的用途，硝普钠对于吲哚胺2,3‑双加氧酶‑1的抑制作用，对IDO1在疾病发生发展中的促进作用进行阻碍和/或破坏，从而为治疗IDO1介导的疾病提供良好的前景。
Description
技术领域
本发明涉及硝普钠（sodium nitroprusside）作为吲哚胺2,3-双加氧酶-1（IDO1）的新用途及其在制备治疗IDO1介导的疾病中的应用。
背景技术
吲哚胺2,3-双加氧酶-1 [EC 1.13.11.17]（IDO1）是一种在细胞内、单体的含血红素蛋白质，催化l-色氨酸 (Trp) 分解代谢成犬尿氨酸途径的第一步。IDO1代谢产物，N-甲酰犬尿氨酸（N-formylkynurenine），进一步代谢成其它生物活性分子。IDO1 在多个组织有表达，包括肺、小肠、胎盘、脾脏及中枢神经。IDO1在许多细胞类型中可由炎性细胞因子（如干扰素γ、大肠杆菌内毒素和肿瘤坏死因子-α等）刺激引起表达。IDO1也在宿主抗原提呈细胞 (APC)、单核细胞-巨噬细胞和肿瘤细胞中表达。
IDO1已作为免疫抑制和耐受性的一种重要机制，在自身免疫性疾病、移植排斥反应中起到重要作用。IDO1通过消耗局部Trp的浓度，抑制T细胞和NK细胞的活性，诱导调节性T细胞的形成。通过这些机制，IDO提供反馈控制的免疫反应。研究发现，如果IDO在卵巢癌、结直肠癌及其他肿瘤细胞中高表达，则肿瘤病人预后较差，因而它可起到肿瘤治疗的预测作用。
IDO1作为靶点也可以在多种肿瘤中起作用。例如，在卵巢癌、大肠癌和子宫内膜肿瘤中，IDO1表达水平升高。在临床前的模型中，IDO1通过抑制抗肿瘤免疫反应促进肿瘤的生长。在这些模型中，小分子抑制剂IDO1可以恢复肿瘤免疫排斥现象和提高常用化疗药物的活性。这些数据支持IDO1抑制剂作为新型抗癌药物，可与现有疗法结合。除了治疗癌症，IDO1抑制剂对其他疾病，如脓毒症诱发低血压、精神分裂症、 阿尔茨海默氏症和帕金森病、白内障也起到作用。这些发现促使对IDO抑制剂药物的开发兴趣，特别是癌症免疫治疗。最广泛研究的IDO抑制剂是1-甲基-色氨酸。最近的实验证明，1-甲基-色氨酸可与大量的临床相关的化疗药物联合使用，起到协同作用。1-甲基-色氨酸与环磷酰胺、顺铂、阿霉素或紫杉醇的组合可以治愈neu诱导的小鼠乳腺癌模型。
目前，国际市场上有几类IDO1抑制剂在临床实验，如新型IDO1抑制剂INCB024360由Incyte公司开发治疗晚期恶性肿瘤。然而，IDO1抑制剂总体上数量仍较少，并且实验室或临床效果仍有待提高。
发明内容
本发明一方面涉及硝普钠或其药学上可接受的盐作为一种吲哚胺2,3-双加氧酶-1抑制剂（IDO1）的用途。
本发明另一方面提供硝普钠或其药学上可接受的盐在制备治疗IDO1介导的疾病的药物中的应用。
在一些实施方式中，所述IDO1介导的疾病是指IDO1表达上调的疾病，包括但不限于，肿瘤、脓毒症诱发低血压、精神分裂症、 阿尔茨海默氏症和帕金森病和白内障。
在一些实施方式中，所述肿瘤选自在卵巢癌、结直肠癌和子宫内膜肿瘤。
硝普钠的结构式如下式所示，现有文献显示其与中药提取物组合物治疗高血压（CN101773657A），并且未曾见其被用于治疗肿瘤相关报道。硝普钠可通过本领域技术人员已知的适当方法制得，一种示例性的制备方法参见中国专利申请公布CN 201110406273.2。
本发明预期硝普钠的“药学上可接受的盐”也具有相同的活性。通常，该盐例如通过将游离酸或碱形式的这些化合物与化学计算量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中制备。通常，非水性介质如乙醚，乙酸乙酯，乙醇，异丙醇或乙腈是优选的。酸加成盐的实例包括无机酸加成盐例如，盐酸盐，氢溴酸盐，氢碘酸盐，硫酸盐，硝酸盐，和有机酸加成盐，如例如乙酸盐，马来酸盐，富马酸盐，柠檬酸盐，草酸盐，琥珀酸盐，酒石酸盐，苹果酸盐，扁桃酸盐和对甲苯磺酸盐。碱加成盐的实例包括无机盐如钠、钾、钙、铵、镁、铝和锂盐；以及有机碱如乙二胺、乙醇胺、N,N-二烷基乙醇胺、三乙醇胺、葡糖胺和碱性氨基酸盐。
本发明证实了硝普钠对于吲哚胺2,3-双加氧酶-1的抑制作用，对IDO1在疾病发生发展中的促进作用进行阻碍和/或破坏，从而为治疗IDO1介导的疾病提供良好的前景。
附图说明
图1是硝普钠对吲哚胺2,3-双加氧酶-1（IDO1）的抑制作用的曲线图。
具体实施方式
本发明现将结合以下实验及附图进一步阐释，需要说明的是，这些实验例及附图不应解释为对本发明的限制。
犬尿氨酸标准曲线绘制
1. 标准培养基（200μL）：20μL 的0.5M磷酸钾缓冲液(pH 6.5)，终浓度为50 mM；20μL的0.2M抗坏血酸，终浓度为20 mM；4μL 的0.5mM亚甲蓝，终浓度为10 μM；4μL 的5mg/ml过氧化氢酶，终浓度为100μg/ml；132 μL的dd-H2O；20μL 的犬尿氨酸溶液，终浓度分别为0, 1,5, 7.5, 10, 25, 50, 75及 100 mM。
2. 加入40μL的1M NaOH溶液后，离心培养基(11,500rpm, 4°C, 15min)。
3. 将200μL的上清液转移至96孔微量滴定板上，测定荧光强度(λex 360nm, λem480nm)。
蛋白质定量
通过BCA法测定蛋白质IDO1含量。在λmax 570nm处测定溶液吸收值，随后以牛血清白蛋白标准曲线（0-2 mg/ml）检查，以获得蛋白质浓度。
活性实验
1. 标准实验培养基（200μL）：20μL 的0.5M磷酸钾缓冲液(pH 6.5)，终浓度为50 mM；20μL 的0.2M抗坏血酸，终浓度为20 mM；4μL 的0.5mM亚甲蓝，终浓度为100 μg/ml；20μL 的2mM左旋色氨酸，终浓度为200 μM；112 μL的dd-H2O；20μL 的IDO1，终浓度为0至10 μg/ml。
2. 对照：以20μL的dd-H2O替代IDO1。
3. 加入40μL的1M NaOH溶液后，混合物60°C孵育15min，以将N-甲酰基犬尿氨酸水解为犬尿氨酸。随后离心培养基(11,500rpm, 4°C, 15min)。
4. 将200μL的上清液转移至96孔微量滴定板上，测定荧光强度(λex 360nm, λem480nm)。
抑制试验
1. 标准实验培养基（200μL）：20μL 的0.5M磷酸钾缓冲液(pH 6.5)，终浓度为50 mM；20μL 的0.2M抗坏血酸，终浓度为20 mM；4μL 的0.5mM亚甲蓝，终浓度为10 μM；4μL 的5mg/ml过氧化氢酶，终浓度为100μg/ml；112 μL的dd-H2O；10μL 的4mM左旋色氨酸，终浓度为200 μM； 20μL 的5 μg/ml IDO1和10 μl在DMSO中的抑制剂（1-甲基-L-色氨酸）溶液，终浓度分别为0, 0.1, 0.5和1mM。
2. 对照（i）：以10μL的dd-H2O替代L-色氨酸。
3. 对照（ii）：以30μL的dd-H2O替代L-色氨酸和IDO1。
4. 加入40μL的1M NaOH溶液后，混合物60°C孵育15min，以将N-甲酰基犬尿氨酸水解为犬尿氨酸。随后离心培养基(11,500rpm, 4°C, 15min)。
5. 将200μL的上清液转移至96孔微量滴定板上，测定荧光强度(λex 360nm, λem480nm)。
6. 以公式(100-(A/Bx100))计算抑制率，其中A表示存在抑制剂时IDO1的活性，B表示不存在抑制剂时IDO1的活性。结果见图1，从图中得到的相关参数见表1。
表1. 硝普钠的抑制作用
| 化合物名称 | IC50(uM) | Hillslope | R square |
| 硝普钠 | 0.2749 | -1.24 | 0.9773 |
Claims (5)
1.硝普钠或其药学上可接受的盐作为吲哚胺2,3-双加氧酶-1抑制剂的用途。
2.硝普钠或其药学上可接受的盐在制备治疗IDO1介导的疾病的药物中的应用。
3.根据权利要求2所述的应用，其中所述IDO1介导的疾病是指IDO1表达上调的疾病。
4.根据权利要求2或3所述的应用，其中所述IDO1介导的疾病选自肿瘤、脓毒症诱发低血压、精神分裂症、阿尔茨海默氏症和帕金森病和白内障。
5.根据权利要求4所述的应用，其中所述肿瘤选自在卵巢癌、结直肠癌和子宫内膜肿瘤。
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