CN101143868A - 醛糖还原酶抑制剂结构及用途 - Google Patents

醛糖还原酶抑制剂结构及用途 Download PDF

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CN101143868A
CN101143868A CNA2007101213255A CN200710121325A CN101143868A CN 101143868 A CN101143868 A CN 101143868A CN A2007101213255 A CNA2007101213255 A CN A2007101213255A CN 200710121325 A CN200710121325 A CN 200710121325A CN 101143868 A CN101143868 A CN 101143868A
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aldose reductase
compound
reductase inhibitor
present
inhibition
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朱长进
许大江
彭佳
王栋
王丹
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Beijing Institute of Technology BIT
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Abstract

本发明公开了一类海因类醛糖还原酶抑制剂结构及用途。本发明所提供的化合物结构为右式，其抑制活性可用于醛糖还原酶抑制剂(ARIs)的合成及对醛糖还原酶(AR)抑制作用的研究，发明所提供的化合物可作为醛糖还原酶抑制剂在治疗糖尿病并发症中应用，并在化学生物学、生物医学及生物工程领域也具有广泛的应用前景。

Description

醛糖还原酶抑制剂结构及用途
技术领域
本发明涉及新颖的醛糖还原酶抑制剂，其制备方法及其对醛糖还原酶(AR)的抑制作用，应用于化学生物学，生物医学及生物工程领域。
背景技术
大量动物和临床实验已证明醛糖还原酶抑制剂(ARIs)对治疗糖尿病并发症非常有效。过去30年中，至少有14种ARIs被证明非常有效并且已通过II期临床。其中最有效的是在日本已上市的Epalrestat、和已进入III期临床的Fidarestat和AS-3201。而其中Fidarestat被证明比已上市的Epalrestat更有效，它在体内的抑制效果要远远高于Epalrestat。目前所有发现的ARIs都主要结合在AR的一个已知催化活性部位。据报道[1]，酶的催化活性部位附近可能存在有非催化活性的结合部位，对这些非活性部位的结合不仅仅可以增强抑制性，而且抑制剂的选择性也会大大增强。基于上述背景，本发明以Fidarestat做为母体结构，设计并合成了一类新型化合物，而且评价、确定了化合物对AR的抑制作用。
发明内容
本发明的目的在于提供一类新的对AR具有较强抑制能力的化合物及其用途。
本发明所提供化合物是化合物2，其结构式为：
Figure A20071012132500031
化合物2的合成方法是将化合物1[2](为已有技术)与对苯二胺以1∶1.2摩尔当量比在DCC催化下发生偶联反应制得。该制备过程可以用分子结构反应式表述如下：
Figure A20071012132500041
反应式中化合物1为(2S，4S)-6-氟-2’，5’-二氧螺[苯并二氢吡喃-4，4’-咪唑烷]-2-羧酸。
本发明的化合物2a的名称、结构及分子量如表1所示。
表1化合物2a的名称、结构及分子量
Figure A20071012132500042
对醛糖还原酶抑制活性测定方法：把从老鼠眼睛提出的AR部分提纯，然后测试了新合成化合物2a，在体外抑制AR活性的能力(如表2所示)，使用fidarestat作为对照化合物。用紫外分光光度计监测反应液在340nm(为AR辅酶NADPH的吸收)处吸光度的变化来测试。
表2化合物2a与fidarestat在体外对鼠晶状体AR的抑制能力
化合物   抑制百分数(％) IC50 a(μM)
  10-8M   3.3×10-8 M   5×10-8M   10-7M   10-6 M   10-5M
2a 13   ---b   ---b   36   40   81   0.42
  fidarestat   26   ---b   42   88   ---b   ---b   0.034
aIC50(μM)(95％C.L.)是在本发明所实施的实验体系中所测得的值b没有在该浓度下测量
本发明所提供的化合物及抑制活性可用于醛糖还原酶抑制剂的合成及对醛糖还原酶抑制作用的研究，可作为醛糖还原酶抑制剂在治疗糖尿病并发症中应用，并在化学生物学，生物医学及生物工程领域具有广泛的应用前景。
具体实施方式
实施例1
化合物2的制备：
根据以前文献[2]中的方法可得原料1，再以原料1制得化合物2
化合物2的制备方法近似，以化合物(2S，4S)-6-氟-2’，5’-二氧螺[苯并二氢吡喃-4，4’-咪唑烷]-2-酰胺基-对苯胺2a的制备为例。
1、将原料1(100mg，0.36mmol)，在THF内溶解，加入HOBt(59mg，0.50mmol，)，然后加入DCC(152mg 0.72mmol)。
2、反应室温搅拌20分钟，加入对苯二胺(46.7mg，0.43mmol)，搅拌5小时后，TLC检查(氯仿/甲醇＝10/1)，紫外下发现Rf＝0.60(对应产物2a)，将反应混合物过滤，滤掉白色沉淀DCU。
3、柱层析(二氯甲烷/甲醇＝25/1)对粗产品进行纯化得到产品2a(64mg，46/％)，淡黄色粉末。
实施中所合成的化合物均经过ESI质谱(MS)，核磁共振谱(1HNMR)分析和元素分析鉴定。
实施本发明化合物对醛糖还原酶抑制活性的步骤：
1、配制缓冲溶液：先分别配制浓度为0.2mol/L的NaH2P04和Na2HP04溶液，然后分别取二者81.5ml，18.5ml用水稀释至终体积为200ml，即得到0.1mol/L pH＝6.2的磷酸盐缓冲溶液。
2、配制浓度为0.104 mM NADPH溶液(以缓冲溶液作为溶剂)。
3、配制浓度为10mM D，L-甘油醛溶液(以缓冲溶液作为溶剂)。
4、从正常杀死的老鼠眼球中迅速取出晶状体，然后在Glas-Potter匀浆器中加入3倍(0.4ml/lens)于其体积的冷去离子水(0-4℃)匀浆。匀浆液在低温离心机中以12000×g转速，0-4℃的温度，离心30min.最后取上清液，即为AR的水溶液，用于酶活测试。
5、在30℃的温度下，在1ml测试比色皿中分别加入0.25mL 0.104mM NADPH，0.25mL0.1M磷酸盐缓冲溶液(pH＝6.2)，0.1mL所提取的酶液，0.15mL去离子水。参照比色皿中加入0.25mL 0.104mM NADPH，0.50mL 0.1M磷酸盐缓冲溶液(pH＝6.2)，0.1mL所提取的酶液，0.15mL去离子水。然后把含有上述混合液的两个比色皿放在30℃条件下，保温10min。最后向测试比色皿中加入0.25mL10mM底物即D，L-甘油醛开始反应，用紫外分光光度计在340nm监测5min。从所得数据，以吸光度为纵轴，时间为横州，可得一直线，求得此直线的斜率，记为I0，代表酶活。酶的活性最佳值是处于NADPH吸光度变化在0.011±0.0010吸光度单位/min的范围内，如果不在此范围，通过稀释酶液来使其达到这一范围。对测试比色皿要加对照比色皿是为了校正由于非酶因素(比如空气中氧气也会氧化NADPH)所导致的NADPH的氧化。
6、化合物抑制百分数的测试同测酶活的方法相似，只是在未加底物时，要在测试比色皿和参照比色皿中各加入5μL的被测化合物溶液。所得直线的斜率记为Ix。然后根据下面的公式计算可得该浓度下的抑制百分数。
I％＝(|I0-Ix|/|I0|)×100％
重复测量不同浓度的化合物溶液，分别计算出相应浓度的抑制百分数，可得到“抑制百分数”对“浓度对数”的直线，然后从图中读出抑制百分数为50％对应的浓度对数，反对数即可得IC50。

Claims (2)

1.醛糖还原酶抑制剂结构及用途，其特征在于：
化合物2的结构为：
Figure A2007101213250002C1
2.如权利要求1所述的醛糖还原酶抑制剂结构及用途，其特征在于：化合物2作为醛糖还原酶抑制剂在治疗糖尿病并发症的应用。
CNA2007101213255A 2007-09-04 2007-09-04 醛糖还原酶抑制剂结构及用途 Pending CN101143868A (zh)

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WO2017223179A1 (en) 2016-06-21 2017-12-28 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
US10639306B2 (en) 2010-07-16 2020-05-05 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and uses thereof
WO2020205846A1 (en) 2019-04-01 2020-10-08 Applied Therapeutics Inc. Inhibitors of aldose reductase
US11590131B2 (en) 2017-07-28 2023-02-28 Applied Therapeutics, Inc. Compositions and methods for treating galactosemia

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10639306B2 (en) 2010-07-16 2020-05-05 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and uses thereof
US11529349B2 (en) 2010-07-16 2022-12-20 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and uses thereof
US11730737B2 (en) 2010-07-16 2023-08-22 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and uses thereof
WO2017223179A1 (en) 2016-06-21 2017-12-28 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
US10150779B2 (en) 2016-06-21 2018-12-11 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
US10647726B2 (en) 2016-06-21 2020-05-12 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
US10870658B2 (en) 2016-06-21 2020-12-22 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
EP3757107A1 (en) 2016-06-21 2020-12-30 The Trustees of Columbia University in the City of New York 4-oxo-3,4-dihydrothieno[3,4-d]pyridazine compounds as aldose reductase inhibitors and methods of use thereof
US11498925B2 (en) 2016-06-21 2022-11-15 The Trustees Of Columbia University In The City Of New York Aldose reductase inhibitors and methods of use thereof
EP4316603A2 (en) 2016-06-21 2024-02-07 The Trustees of Columbia University in the City of New York 4-oxo-3,4-dihydrothieno[3,4-d]pyridazine compounds as aldose reductase inhibitors and methods of use thereof
US11590131B2 (en) 2017-07-28 2023-02-28 Applied Therapeutics, Inc. Compositions and methods for treating galactosemia
WO2020205846A1 (en) 2019-04-01 2020-10-08 Applied Therapeutics Inc. Inhibitors of aldose reductase

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