CN118001283A - 用于预防及治疗糖尿病性肾病的包含腺苷衍生物的药学组合物 - Google Patents
用于预防及治疗糖尿病性肾病的包含腺苷衍生物的药学组合物 Download PDFInfo
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Abstract
本发明提供一种用于预防或治疗糖尿病性肾病的药学组合物。根据本发明,用于预防或治疗糖尿病性肾病的药学组合物包含腺苷衍生物化合物或其药学上可接受的盐作为有效成分。
Description
本申请是基于申请号为201880045444.3(国际申请号为PCT/KR2018/007717),国际申请日为2018年07月06日,发明名称为“用于预防及治疗糖尿病性肾病的包含腺苷衍生物的药学组合物”的中国专利申请提出的分案申请。
技术领域
本发明涉及一种有效地使用于预防或治疗糖尿病性肾病(diabeticnephropathy)的包含腺苷衍生物的药学组合物。
背景技术
慢性肾脏疾病(chronic kidney disease,CKD)在世界范围内被认为是一种严重的疾病。在最近的几十年中,疾病的发病和死亡的主要原因正在转向营养过剩/缺乏和进行性的慢性炎症性疾病。慢性肾脏疾病发病率的增加正是这一转变的一种体现(非专利文献001.斯基耶帕蒂A,&雷姆兹G(Schieppati A,&Remuzzi G))。将经历需要如透析或移植等肾脏替代疗法的慢性肾脏疾病的患者的状态称为终末期肾脏病(end stage renal disease,ESRD)。
作为慢性肾脏疾病的一种的糖尿病性肾病(diabetic nephropathy,DN)是由糖尿病而诱发的并发症,其具体指:肾脏的肾小球因高血糖而受到损伤,导致肾小球滤过率降低,并出现蛋白尿等肾脏功能下降的疾病。这种糖尿病性肾病在需要透析的终末期肾脏疾病患者的病因中占有最大比例,从而其严重性逐渐显现。
尽管还没有批准的用于治疗糖尿病性肾病的药物,但是以缓解症状为目的单独使用血管紧张素受体阻滞剂(ARB)和血管紧张素转化酶(ACE)抑制剂或其联合给药的疗法广泛被应用(非专利文献002,布兰诺BM,库珀ME等;非专利文件003,路易斯EJ,LG等;非专利文件004,纳考N,吉村A等;非专利文件005,麦金农M,苏拉S等)。但是,这些治疗剂仅能在一部分慢性肾脏疾病患者中有延迟终末期肾病的发作或抑制肾小球滤过率(GFR)的减少的效果,但对大多数慢性肾脏疾病患者来说,其效果微乎其微(6.比拉约尔E和哈里斯DCH)。
因此,作为新的治疗剂而提出了如下述化学式A的腺苷衍生物,其能够克服肾素-血管紧张素系统(renin-angiotensin system,RAS)抑制剂的局限。
[化学式A]
据报道,在输尿管梗阻动物肾脏中,上述腺苷衍生物具有有效抑制上皮-间质转化(EMT)和细胞外基质(ECM)的蓄积,并抑制由TGF-β1引起的胶原ImRNA表达的效果,从而具有预防或治疗慢性肾脏疾病和肾纤维化的效果。
但是,上述腺苷衍生物中存在几种局限性,首先,上述腺苷衍生物的功效数据是通过单侧输尿管梗阻(UUO)模型来获得的结果,虽然单侧输尿管梗阻模型在肾纤维化的机制或抗纤维化的药物筛选方面是良好实验模型,但是不适合作为治疗糖尿病引起的肾脏疾病的实验模型,因此,存在上述腺苷衍生物对糖尿病性肾脏疾病是否具有显著功效的不确定性的问题。
由此,本发明人首次研发了将腺苷A3受体(A3AR)拮抗剂作为糖尿病性肾病的预防和治疗剂,并且通过合成出具有抑制糖尿病性肾病(如肾小球损伤,蛋白尿等)的作用以及药动学(PK)特性(如体内吸收率,生物利用度等)优异的新型腺苷衍生物化合物而完成了本发明。
发明内容
发明所要解决的问题
本发明所要解决的技术问题在于,提供一种能够预防或治疗糖尿病性肾病的包含腺苷衍生物的药学组合物,其中上述腺苷衍生物起到腺苷A3受体拮抗剂的作用。
本发明所要解决的问题不仅限于上述技术问题,并且本领域技术人员从以下描述中可以清楚地理解未提及的其他技术问题。
用于解决问题的方案
为了解决上述问题,根据本发明的一实施例的用于预防或治疗糖尿病性肾病(diabetic nephropathy)的药学组合物包含由化学式1来表示的化合物或其药学上可接受的盐作为有效成分。
[化学式1]
(上述式中,A是O或者S;R是未取代、或独立或选择性地被一个或两个以上的C6-C10芳基取代的直链C1-C5的烷基或支链C1-C5的烷基;未取代、或独立或选择性地被卤素及一个或两个以上的直链或支链C1-C4烷氧基取代、或羟羰基取代的苄基;Y是H或者卤素元素。)
上述糖尿病性肾病可以是由1型糖尿病和2型糖尿病中的至少一种引起的。
由上述化学式1来表示的化合物可以是由下述化学式B来表示的化合物。
[化学式B]
为了解决上述问题,根据本发明的用于预防或治疗糖尿病性肾病的口服剂包含由下述化学式1来表示的化合物或其药学上可接受的盐。
[化学式1]
(上述式中,A是O或者S;R是未取代、或独立或选择性地被一个或两个以上的C6-C10芳基取代的直链C1-C5的烷基或支链C1-C5的烷基;未取代、或独立或选择性地被卤素及一个或两个以上的直链或支链C1-C4烷氧基取代、或羟羰基取代的苄基;Y是H或者卤素元素。)
上述糖尿病性肾病可以是由1型糖尿病和2型糖尿病中的至少一种引起的。
上述口服剂还可以包含从由甲基纤维素(Methyl cellulose,MC)、二甲基亚砜(Dimethy sulfoxide,DMSO)、聚乙二醇(Polythyleneglycol,PEG)及蒸馏水组成的组中选择的至少一种赋形剂。
作为赋形剂上述口服剂可以包含0.5wt%甲基纤维素。
上述由化学式1来表示的化合物或其药学上可接受的盐可以以粉末状态填充于胶囊内。
上述由化学式1来表示的化合物可以是由下述化学式B来表示的化合物。
其他实施例的具体详情包含于详细说明及附图中。
发明效果
本发明的腺苷衍生物可以作为预防或治疗诱发肾小球损伤或蛋白尿的糖尿病性肾病的腺苷A3受体拮抗剂而起到作用,因此非常适用于预防和治疗糖尿病性肾病。
另外,当口服给药时,药物的吸收优异,几乎没有体内毒性,因此具有生物相容性(biocompatible),并且剂型化为口服剂时,其储存稳定性优异,因此可作为用于预防及治疗糖尿病性肾病的适于口服给药的药学组合物来使用。
根据本发明的实施例的效果不仅限于以上示例的内容,本说明书中包含有更多种效果。
附图说明
图1是观察实验例1中实验动物的肾小球及肾小球系膜的组织学变化的图。
图2是示出在实验例1中对实验动物的肾小球体积和肾小球系膜截面积变化进行测量的结果的图。
图3是示出在实验例1中对实验动物的糖尿病性肾脏损伤的指标进行测量的结果的图。
图4是示出在实验例2中对实验动物的蛋白尿及肾小管损伤程度进行测量的结果的图。
图5是观察实验例2中实验动物的肾小球的损伤程度的图。
图6是在实验例2中测量实验动物的肾小球体积及肾小球系膜的面积的图。
图7是示出在实验例2中观察实验动物的肾脏的纤维化程度的图及对肾脏的纤维化面积进行测量的结果的图。
图8是示出在实验例2中针对实验动物的肾脏纤维化的指标(胶原蛋白IV、PAI-1及TGF-β)进行mRNA表达量测量的结果的图。
图9是在实验例2中通过免疫染色来观察实验动物的肾脏中的炎症反应程度的图。
图10是示出在实验例2中针对实验动物的炎症反应指标(MCP-1,TNF-α,NLRP3 andF4/80)进行mRNA表达量的测量的结果的图。
图11是在实验例2中通过免疫染色示出用作氧化应激指标的8-oxo-dG的免疫染色及面积的图。
图12是示出在实验例2中对作为氧化应激指标的LPO在肾组织及尿中的含量进行测量的结果的图。
图13是观察实验例2中的实验动物的肾脏的脂质蓄积程度的图。
图14是示出实验例2中利用油红O(Oil-Red O)在实验动物肾脏中测量脂质蓄积的面积的结果的图。
图15至图17是示出在实验例3中针对实验动物分别测量尿中白蛋白值、裂孔膜相关蛋白值及8-异前列腺素(8-isoprostan)的值的结果的图。
图18及图19是示出在实验例3中针对实验动物的肾脏的炎症反应和纤维化减少程度的组织学特征及针对相关指标的mRNA表达量的图。
图20是在来自于实验室培养的小鼠的肾小球足细胞及肾小管上皮细胞的培养液中添加高葡萄糖、血管紧张素II和游离脂肪酸来诱发炎症及纤维化反应之后施用化学式B的化合物,由此观察炎症及纤维化反应是否被抑制的结果。
具体实施方式
如果参照附图和与以下详细描述的实施例,那么本发明的优点及特征以及实现他们的方式会变的明确。但是,本发明并不仅限于以下公开的实施例,而是能以相互不同的多种形态来实现,并且,本实施例仅仅是为了使本发明的公开完整,并将发明的范围充分的传达给本发明所属技术领域的技术人员而提供的,另外,本发明仅由权利要求书的范围所定义。
本发明中的术语“药学上可接受的盐”意味着该技术领域中根据常规方法制造的盐,这样的制造方法是技术人员所公知的。具体地,上述药学上可接受的盐包括衍生自在药理学或生理学上可接受的以下无机酸和有机酸及碱的盐,但不限于此。合适的酸的例子包括盐酸、溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、2-萘磺酸、苯磺酸等。由适当的碱衍生的盐可以包括碱金属,例如,钠或钾;碱土金属,例如镁。
本发明中使用的术语“1型糖尿病”是指胰腺中不能生成胰岛素或仅分泌少量,导致不能调节血糖的状态(胰岛素依赖型糖尿病),“2型糖尿病”是指所分泌的胰岛素无法正常发挥功能,导致高血糖的状态持续(非胰岛素依赖型糖尿病)。
在本发明中,“预防”是指通过将该组合物进行给药来抑制糖尿病性肾病的症状或延迟发病的所有作用,并且“治疗”是指通过将该组合物进行给药来改善或有益地改变糖尿病性肾病的症状的所有作用。
在本发明中使用的术语“氯沙坦(losartan)”作为具有由化学式C表示的(2-丁基-4-氯-1-{[2'-(1H-四唑-5-基)联苯-4-基]甲基}-1H-咪唑-5-基}甲醇的化学结构的血管紧张素II受体拮抗剂,虽然通常被广泛用作高血压治疗剂,上述“氯沙坦”也用于减缓糖尿病性肾病的进展的物质。
[化学式C]
以下,对本发明进行详细地说明。
本发明提供一种包含由化学式1来表示的化合物或其药学上可接受的盐作为有效成分的腺苷衍生物。
[化学式1]
上述式中,
A是O或者S;
R是未取代、或独立或选择性地被一个或两个以上的C6-C10芳基取代的直链C1-C5的烷基或支链C1-C5的烷基;未取代、或独立或选择性地被卤素及一个或两个以上的直链或支链C1-C4烷氧基取代、或羟羰基取代的苄基;
Y是H或卤元素。
优选地,
上述A是O或者S;
上述R是甲基;乙基;丙基;萘基甲基(naphthylmethyl);苄基;独立或选择性地由选自F、Cl、Br、I及C1~C3烷基中的一个或两个以上的取代基取代的苄基;或甲苯酸(toluicacid);
上述Y是H或Cl。
更优选地,
上述A是O或S,
上述R是甲基、乙基、1-萘基甲基、苄基、2-氯苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-碘苄基、2-甲氧基-5-氯苄基、2-甲氧基苄基或3-甲苯酸;
上述Y是H或Cl。
根据本发明的由化学式1来表示的腺苷衍生物的优选例,如下:
1)(2R,3R,4S)-2-(2-氯-6-(3-氟苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
2)(2R,3R,4S)-2-(2-氯-6-(3-氯苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
3)(2R,3R,4S)-2-(6-(3-溴苄基氨基)-2-氯-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
4)(2R,3R,4S)-2-(2-氯-6-(3-碘苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
5)(2R,3R,4S)-2-(2-氯-6-(2-氯苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
6)(2R,3R,4S)-2-(2-氯-6-(5-氯-2-甲氧基苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
7)(2R,3R,4S)-2-(2-氯-6-(2-甲氧基苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
8)(2R,3R,4S)-2-(2-氯-6-(萘-1-基甲基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
9)3-((2-氯-9-((2R,3R,4S)-3,4-二羟基四氢噻吩-2-基)-9H-嘌呤-6-基氨基)甲基)苯甲酸;
10)2-(2-氯-6-甲基氨基-嘌呤-9-基)四氢噻吩-3,4-二醇;
11)(2R,3R,4S)-2-(6-(3-氟苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
12)(2R,3R,4S)-2-(6-(3-氯苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
13)(2R,3R,4S)-2-(6-(3-溴苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
14)(2R,3R,4S)-2-(6-(3-碘苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇;
15)(2R,3R,4R)-2-(6-(3-溴苄基氨基)-2-氯-9H-嘌呤-9-基)四氢呋喃-3,4-二醇;及
16)(2R,3R,4R)-2-(2-氯-6-(3-碘苄基氨基)-9H-嘌呤-9-基)四氢呋喃-3,4-二醇。
根据本发明的腺苷衍生物可以按照授权专利第10-1396092号中记载的方法来合成。
根据本发明的由化学式I表示的腺苷衍生物可以以药学可接受的盐的形态来使用。作为上述盐可使用由各种药学可接受的有机酸或无机酸形成的酸加成盐。可以使用的适合的有机酸包括,例如羧酸、膦酸、磺酸、乙酸、丙酸、辛酸、癸酸、乙醇酸、乳酸、富马酸、琥珀酸、己二酸、苹果酸、酒石酸、柠檬酸、谷氨酸、天冬氨酸、马来酸、苯甲酸、水杨酸、苯二甲酸、苯乙酸、苯磺酸、2-萘磺酸、甲基硫酸(methylsulfuric acid)、乙基硫酸(ethylsulfuric acid)、月桂基硫酸(dodecylsulfuric acid)等;并且,作为适合的无机酸可使用例如盐酸、硫酸等氢卤酸或磷酸等。
根据本发明的由上述化学式1来表示的腺苷衍生物不仅可以包括药学上可接受的盐,还可以包括能够通过常规方法来制造的所有盐、水合物及溶剂化物。
本发明提供一种含有腺苷衍生物作为有效成分的用于预防和/或治疗糖尿病性肾病(diabetic nephropathy)的药学组合物,其中,上述腺苷衍生物包含由化学式1来表示的化合物和/或其药学上可接受的盐。
上述糖尿病性肾病可以由1型糖尿病和2型糖尿病中的至少一种而引起。
上述糖尿病性肾病不仅可以包括如肾小球及肾小球系膜损伤、肾小管损伤、蛋白尿、肾脏纤维化、炎症、氧化应激和脂质蓄积等肾脏损伤,还可以包括引起其的所有疾病、疾患、症状等。
由上述化学式1来表示的腺苷衍生物的优选例可以是由化学式B来表示的化合物的(2R,3R,4S)-2-(2-氯-6-(3-氯苄基氨基)-9H-嘌呤-9-基)四氢噻吩-3,4-二醇。
[化学式B]
本发明的预防和/或治疗糖尿病性肾病的药物组合物可以剂型化为口服剂。
根据本发明的预防和/治疗糖尿病性肾病的口服剂包含由上述化学式1来表示的化合物和/或其的药学上可接受的盐,并且,进一步地,还可以包括赋形剂。
上述糖尿病性肾病可以由1型糖尿病和2型糖尿病中的至少一种而引起。
上述赋形剂可以为选自由甲基纤维素(Methy Cellulose,MC)、二甲基亚砜(Dimethysulfoxide,DMSO)、聚乙二醇(Polyethyleneglycol,PEG)、蒸馏水(Distilledwater,DW)、胶囊剂等组成的组中的一种或多种。上述赋形剂的优选例可以是0.5wt%的甲基纤维素。
口服剂可以是由上述化学式1来表示的化合物和/或其药学上可接受的盐以粉末形式或溶解于赋形剂的溶液形式填充于胶囊内。
上述由化学式1来表示的化合物可以是由下述化学式B来表示的化合物。
[化学式B]
本发明的用于预防和/或治疗糖尿病性肾病的药学组合物可以口服给药于患者。优选给药量可以通过考虑患者的状态及体重、疾病程度、药物形式、给药途径及时间等多种因素来适当的进行选择。
由于本发明的腺苷衍生物在利用先天性诱导糖尿病的动物模型的实验中显示出对肾小球损伤及肾小球系膜损伤、肾小管损伤、蛋白尿、肾脏纤维化、炎症、氧化应激及脂质蓄积等糖尿病性肾脏损伤的抑制功效(参照实验例1及2),并在损伤分泌胰岛素的细胞而导致的胰岛素缺乏性1型糖尿病性肾脏损伤也显示出抑制功效,因此,可以用作预防和/或治疗糖尿病性肾病的非常合适的药学组合物。
优选实施例
以下,为了帮助对本发明的理解,通过实施例对本发明进行详细地说明。然而,下述的实施例仅是为了向本领域技术人员进行完整的说明而提供,并且,仅仅用于示例本发明的内容,因此本发明的范围不仅限于下述实施例。
<实验例1>本发明的腺苷衍生物对2型糖尿病性肾脏损伤的抑制功效实验(1)
为了了解本发明的腺苷衍生物的抑制肾脏损伤的功效而在2型糖尿病模型中执行了如下动物实验。
将化学式B的化合物分别以每日1.5mg/kg、5mg/kg和10mg/kg的剂量给药于通过瘦素受体(leptin receptor)基因的点突变而先天性地诱发2型糖尿病的8周龄db/db糖尿病小鼠,共给药12周。给药12周后,摘取溶剂对照组和实验物质给药组的肾脏,观察肾小球(glomerular)的组织学变化,并且将尿中白蛋白(albumin)和脂质过氧化物(lipidperoxide,LPO)的值,或针对裂孔膜相关蛋白(nephrine)、NGAL、TGF-β、胶原蛋白(Collagen)IV、纤连蛋白(fibronectin)、MCP-1和ICAM-1的mRNA表达量设置为肾脏损伤的指标,从而对肾脏的保护效果进行测量。另外,将未诱发糖尿病的Db/m小鼠作为对照组,仅施用溶剂,并观察和测量上述项目。
上述各指标中,尿中白蛋白值意味着蛋白尿;裂孔膜相关蛋白的减少意味着足细胞的损伤;NGAL的增加意味着肾小管损伤;TGF-β的增加意味着纤维化;炎性细胞因子(MCP-1,ICAM-1)的增加意味着炎症反应;LPO值意味着氧化应激。
将肾脏组织进行高碘酸希夫(periodic Acid Schiff,PAS)染色后,每组随机选择50个,并通过图像分析仪进行定量和统计,由此实施对肾小球的形态学分析,并且利用电泳和酶联免疫吸附法(Enzyme-Linked Immunosorbent Assay,ELISA)来检测出尿中白蛋白,并且通过实时(real time)PCR来分析mRNA表达。
图1是观察根据上述实验的肾小球及肾小球系膜(mesangial)的组织学变化的图;图2是示出对肾小球的体积(volume)和肾小球系膜的截面积(fractional area)变化进行测量的结果的图;图3是示出对上述糖尿病性肾脏损伤的指标进行测量的结果的图。
图2及图3中db/m表示正常小鼠;db/db表示仅施用溶剂的糖尿病小鼠;db/db+LJ2698(1.5mg/kg)、db/db+LJ2698(5mg/kg)和db/db+LJ2698(10mg/kg)分别显示为将化学式B的化合物分别以每日1.5mg/kg、5mg/kg和10mg/kg的方式给药的糖尿病小鼠(共12周)。
首先,参照图1及图2可以确认,在施用本发明的腺苷衍生物(化学式B的化合物)的糖尿病小鼠中肾小球肥大和血管间质扩张得到了显著的抑制。
另外,参照图3可以确认,尿中白蛋白值或裂孔膜相关蛋白、NGAL、TGF-β、胶原蛋白IV等针对肾脏损伤的指标以与本发明的腺苷衍生物(化学式B的化合物)的给药量依赖性地被抑制。
<实验例2>本发明的腺苷衍生物对2型糖尿病性肾脏损伤的抑制功效实验(2)
为了比较本发明的腺苷衍生物和作为缓解糖尿病性肾病症状为目的而使用的氯沙坦(Losartan)的治疗功效,进行了如下动物实验。
将化学式B的化合物及氯沙坦,分别以每日10mg/kg和1.5mg/kg的用量口服给药于未诱发糖尿病的8周龄的正常db/m小鼠和诱发糖尿病的8周龄的db/db糖尿病小鼠,共给药12周。通过摘取溶剂对照组和药物给药组的肾脏来观察包括肾小球的肾脏的组织学变化,并针对肾脏损伤的指标变化(如蛋白尿、肾小球滤过率降低、肾小管损伤、肾小球肥大、肾脏纤维化、炎症反应、氧化应激及脂质蓄积等)进行了比较。
将肾脏组织进行PAS染色后,每组随机选择50个,并通过图像分析仪进行定量和统计,由此实施了对包括肾小球的肾脏的形态学分析;并且利用电泳和ELISA来检测尿中白蛋白和LPO;mRNA的表达是通过实时(real time)PCR来进行定量分析;通过利用碱性苦味酸动力学(jaffe)法测量血中和尿中肌酐(Creatinine)来计算肾小球滤过率;利用免疫印迹(western blot)、ELISA及免疫组织化学染色法来检测肾脏内蛋白质变化。
图4是示出根据上述实验对蛋白尿及肾小球滤过率减少程度进行测量的结果的图;图5是观察肾小球及肾小管的损伤程度的图;图6是测量肾小球及肾小球系膜的体积和面积的图。
图7是根据上述实验观察肾脏的纤维化程度的图;图8是示出针对肾脏纤维化的指标(胶原蛋白IV、PAI-1、TGF-β及天狼猩红(picrosirius red))进行mRNA表达量测量的结果的图。
图9是根据上述实验观察肾脏炎症反应程度的图;图10是示出针对炎症反应指标(MCP-1、TNF-α、NLRP3及F4/80)进行mRNA表达量测量的结果的图。
图11是根据上述实验对用作肾脏氧化应激指标之一的8-oxo-dG的量进行比较的图;图12是示出对作为另一种氧化应激指标的LPO在肾脏内含量及尿中含量进行测量的结果的图。
图13是根据上述实验观察肾脏的脂质蓄积程度的图;图14是示出通过油红O染色对脂质的面积进行测量的结果的图。
图4至图14中,db/m及db/db分别表示向其施用化学式B的化合物的溶剂(0.25%CMC)的小鼠;db/m+LJ2698和db/db+LJ2698分别表示进行化学式B的化合物给药(共12周)的正常小鼠及糖尿病小鼠;db/db+氯沙坦(Losartan)表示进行氯沙坦给药(共12周)的糖尿病小鼠。
首先,参照图4至图6可以确认,施用本发明的腺苷衍生物(化学式B的化合物)的糖尿病小鼠中的蛋白尿、肾小球滤过率减少、肾小管损伤及肾小球肥大均被抑制,其抑制水平以与施用RAS抑制剂的氯沙坦的糖尿病小鼠类似。
另外,参照图7至图14,当施用本发明的腺苷衍生物(化学式B的化合物)和氯沙坦时,也以类似的水平抑制了患有2型糖尿病的小鼠的肾纤维化、炎症反应、氧化应激、脂质蓄积。
通过上述实验例1和实验例2可以确认,本发明的腺苷衍生物对蛋白尿、肾小球肥大、肾脏纤维化等糖尿病性肾脏损伤显示出给药量依赖性的功效,其程度类似于RAS抑制剂。
<实验例3>本发明的腺苷衍生物对1型糖尿病性肾脏损伤的抑制功效实验(1)
为了了解对肾脏损伤的抑制功效,通过将本发明的腺苷衍生物施用于1型糖尿病模型动物中来执行如下述动物实验。
将链脲佐菌素(Streptozotocin,STZ)给药于正常小鼠,共给药5天,使其诱发1型糖尿病。之后,将小鼠分为将化学式B的化合物以每天10mg/kg的量进行给药的组、将ARB的一种的LC158809以每天1.5mg/kg的量进行给药的组以及每天用10mg/kg的化学式B的化合物和1.5mg/kg的LC158809进行联合给药的组,共给药12周。以未施用链脲佐菌素的正常小鼠、施用链脲佐菌素后仅施用12周溶剂的糖尿病小鼠、以及施用链脲佐菌素后施用12周试验物质的糖尿病小鼠为对象,对肾脏功能及肾脏的组织学变化等进行了确认。
图15至图17是分别示出根据上述实验对尿中白蛋白值、裂孔膜相关蛋白值及8-异前列腺素(8-isoprostan)值进行测量的结果的图。尿中白蛋白值、裂孔膜相关蛋白值及8-异前列腺素值分别作为蛋白尿、肾小球足细胞(podocyte)损伤及氧化应激的指标而被测量。
图18及图19示出针对肾脏的炎症反应及纤维化减少程度的组织学特征及针对关联指标的mRNA表达量的图。
图15至图19中对照组(Control)及STZ表示正常小鼠及诱发1型糖尿病的小鼠;STZ+ARB,STZ+LJ2698和STZ+ARB+LJ2698分别表示将化学式B的化合物、LC158809及化学式B的化合物+LC158809(联合给药)施用12周后的糖尿病小鼠。
参照图15至图17,施用本发明的腺苷衍生物(化学式B的化合物)和ARB(LC158809)的糖尿病小鼠中尿中白蛋白值、裂孔膜相关蛋白值及8-异前列腺素值都有效的减少。通过此结果可以确认,化学式B的化合物是通过与ARB不同的机制来显示药效,因此,可以确认其具有作为对ARB没有反应或对ARB显示出耐药性的患者的替代剂而使用的可能性。
尤其,如图15及图17所示,在联合使用本发明的腺苷衍生物(化学式B的化合物)和ARB(LC158809)的组中作为蛋白尿和氧化应激的指标的尿中白蛋白值和8-异前列腺素值的减少水平更加显著,这显示通过联合施用本发明的腺苷衍生物和ARB来显示出协同效果,并且显示出当联合施用本发明的腺苷衍生物和ARB时具有附加的肾脏保护效果。
参照图18及图19可以确认,施用本发明的腺苷衍生物(化学式B的化合物)的糖尿病小鼠和施用ARB(LC158809)的糖尿病的小鼠中肾脏的炎症反应及纤维化均显著的减少。
<实验例4>利用培养细胞的本发明腺苷衍生物的对肾脏损伤的抑制功效实验(2)
为了了解本发明的腺苷衍生物对培养细胞的抗炎及抗纤维化功效,而进行了如下体外实验。
图20是通过将高浓度葡萄糖、血管紧张素II及游离脂肪酸添加于来自实验室培养的小鼠的肾小球足细胞及肾小管上皮细胞的培养液中,从而诱发MCP-1、NOX4、胶原蛋白(collagen)IV等炎症及纤维化反应后,施用化学式B的化合物来观察炎症及纤维化反应是否被抑制的结果。在两种培养细胞中确认了均具有抗氧化(NOX4)效果、抗纤维化(胶原蛋白IV)效果及抗炎效果(裂孔膜相关蛋白、MCP-1)。
尽管通过参照以上附图对本发明的实施例进行了说明,但是在本发明所属的技术领域技术人员应该理解,在不改变本发明的技术思想或必要技术特征的情况下可以通过其他具体形式来进行实施。因此,应该理解为以上描述的实施例在所有方面都是示例性的而不是限定性的。
Claims (7)
1.一种药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
包含由下述化学式1来表示的化合物或其药学上可接受的盐作为有效成分,
[化学式1]
所述式中,
A是O或者S;
R是i)未取代、或被一个以上的C6-C10芳基取代的直链或支链C1-C5的烷基;ii)未取代、或被一个以上的F、Br、I或直链或支链C1-C4烷氧基取代的苄基;或者iii)被羟羰基取代的苄基;
Y是H或者卤素元素。
2.根据权利要求1所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
所述糖尿病性肾病是由1型糖尿病及2型糖尿病中的至少一种引起的。
3.根据权利要求1所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
所述R是甲基;乙基;丙基;萘基甲基;苄基;被选自F、Br、I及甲氧基中的一个以上取代的苄基;或甲苯酸,
所述Y是H或Cl。
4.根据权利要求1所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
所述药学组合物是口服用组合物。
5.根据权利要求4所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
所述口服用组合物还包括:选自甲基纤维素、二甲基亚砜、聚乙二醇及蒸馏水中的至少一种赋形剂。
6.根据权利要求5所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
所述口服用组合物包含0.5wt%甲基纤维素作为赋形剂。
7.根据权利要求4所述的药学组合物在制备用于预防或治疗糖尿病性肾病的药物中的应用,其特征在于,
由所述化学式1来表示的化合物或其药学上可接受的盐以粉末状态填充于胶囊内。
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US20170216244A1 (en) * | 2014-03-06 | 2017-08-03 | Yale University | Methods for treating diabetic nephropathy |
KR101820909B1 (ko) * | 2017-07-07 | 2018-01-23 | 퓨쳐메디신 주식회사 | 아데노신 유도체를 포함하는 만성신장질환 예방 및 치료용 약학적 조성물 |
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2017
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AU2018297009A1 (en) | 2020-03-05 |
CN110869030A (zh) | 2020-03-06 |
US20200289511A1 (en) | 2020-09-17 |
EP4234021A3 (en) | 2023-09-27 |
JP6965429B2 (ja) | 2021-11-10 |
KR101820909B1 (ko) | 2018-01-23 |
EP3650029A1 (en) | 2020-05-13 |
CA3069118C (en) | 2022-05-31 |
EP4234021A2 (en) | 2023-08-30 |
EP3650029B1 (en) | 2023-06-28 |
JP2020526526A (ja) | 2020-08-31 |
AU2018297009B2 (en) | 2021-10-07 |
CA3069118A1 (en) | 2019-01-10 |
JP2022017355A (ja) | 2022-01-25 |
CN110869030B (zh) | 2024-03-01 |
US11266644B2 (en) | 2022-03-08 |
WO2019009674A1 (ko) | 2019-01-10 |
EP3650029A4 (en) | 2021-05-05 |
US20220143017A1 (en) | 2022-05-12 |
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