CN109125301A - 一种二萜类化合物在制备治疗糖尿病或肥胖症的药物中的用途 - Google Patents

一种二萜类化合物在制备治疗糖尿病或肥胖症的药物中的用途 Download PDF

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CN109125301A
CN109125301A CN201710456144.1A CN201710456144A CN109125301A CN 109125301 A CN109125301 A CN 109125301A CN 201710456144 A CN201710456144 A CN 201710456144A CN 109125301 A CN109125301 A CN 109125301A
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diterpene
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obesity
drug
ptp1b
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郭跃伟
李佳
龚景旭
叶飞
姚励功
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

本发明涉及一种式(Ⅰ)所示的二萜类化合物在制备蛋白酪氨酸磷酸酶抑制剂中的用途及其在制备抗糖尿病或治疗肥胖症的药物中的用途。

Description

一种二萜类化合物在制备治疗糖尿病或肥胖症的药物中的 用途
技术领域
本发明属于医药技术领域。具体而言，涉及一种具有良好的抑制蛋白酪氨酸磷酸酶(PTP1B)活性的二萜类化合物在制药中的用途，尤其涉及在研发和制备抗糖尿病和/或治疗肥胖症的药物中的用途。
背景技术
糖尿病是一种由于胰岛素缺乏或胰岛素功能缺陷所致慢性疾病，该类疾病是以高血糖为特征，而高血糖症状则是由胰岛素分泌缺陷或其生物作用受损，或两者兼有引起的。针对糖尿病药物的研发一直是制药业关注的热点。目前，针对糖尿病治疗的新靶点药物有：GKA激动剂、PTP1B抑制剂、GPR-40激动剂及GPR119激动剂等。其中PTP1B抑制剂在上世纪末为研发的热门靶点，但到目前为止仍未有针对此靶点的药物上市。而且报道的该靶点研究项目和进入临床的候选药物越来越少。根据调研，当前在研的PTP1B抑制剂有：ISI制药公司的ISIS-PTP1BRx已进入II期临床；TransTech Pharma开发的TTP-814也已进入I/II期临床。想要在PTP1B这一靶点的开发上有所作为，还要承担靶点本身所带来的风险，包括PTP1B的多靶点性所带来的风险、解除胰岛素和瘦素信号负调控对控制血糖和体重是否足够有效等，因此对PTP1B抑制剂的研究颇具挑战性。基于此，通过对广泛的化合物类型进行活性筛选和深入的构-效关系研究，从而发现具有PTP1B抑制活性的苗头化合物甚至先导化合物迫在眉睫。
发明内容
式(I)所示的二萜类化合物(命名为Xishacorene A)的PTP1B抑制活性测试表明，其具有良好的PTP1B抑制活性：
因此，本发明提供了式(I)所示的二萜类化合物在制备蛋白酪氨酸磷酸酶抑制剂中的用途。
本发明还提供了一种抑制蛋白酪氨酸磷酸酶(PTP1B)活性的方法，其包括向有此需要的对象施用所述二萜类化合物。所述对象可以为人或动物，细胞或酶。
PTP1B是公知的治疗糖尿病和/或肥胖症的靶点，可以用于治疗糖尿病和/或肥胖症。因此，本发明还提供了式(I)所示的二萜类化合物在制备治疗糖尿病和/或肥胖症的药物中的用途。
本发明进一步提供了一种治疗糖尿病或肥胖症的方法，其包括向有此需要的患者施用所述二萜类化合物。所述患者可以是人或动物。
具体实施方式
下面结合实施例，对本发明做进一步说明，但本发明并不仅限于此。
实施例1二萜类化合物Xishacorene A的制备
(1)短指软珊瑚(Sinularia polydactyla)样品于2013年采自中国南海西沙海域，采集后冷冻保存，直接剪碎，用丙酮浸泡提取4次，合并提取液，减压浓缩得到丙酮(国药集团化学试剂有限公司，中国)粗提物，用无水乙醚(国药集团化学试剂有限公司，中国)将粗提物萃取至上清液无色，减压浓缩得到无水乙醚浸膏。
(2)将无水乙醚浸膏进行硅胶柱层析(200-300目，青岛海洋化工有限公司，中国)处理，用有机溶剂石油醚-乙醚(体积比约100:0、约95:5、约8:2、约7:3、约6:4、约3:7)(国药集团化学试剂有限公司，中国)进行梯度洗脱，收集体积比约95：5部分的洗脱组分；将收集的洗脱组分再经过凝胶柱层析(Pharmacia,USA，Sephadex LH20)和高效液相(RP-HPLC)(ODS-HG-5半制备色谱柱[5μm,250×9.4mm])，高效液相的洗脱液为乙腈/水(体积比)95:5，洗脱速度为3.0mL/min，即得该具有新颖骨架的二萜类化合物(Xishacorene A)，经波谱解析，具有化学式(I)所示的结构：
式(I)化合物的理化性质：
0.91(3H,s),1.07(3H,s),1.41-1.44(2H,m),1.51(1H,m),1.57-1.70(4H,m),1.70(3H,s),1.73(3H,s),1.85(3H,s),1.87(1H,t,J＝2.4Hz),5.05(2H,m),5.27(1H,m),5.39(1H,d,J＝15.3Hz),5.71(1H,d,J＝11.4Hz),5.92(1H,dd,J＝11.0,17.7Hz),6.01(1H,dd,J＝11.4,15.3Hz)ppm；质谱数据：HREIMS:m/z 270.2361.
NMR测试以MeOD(δH 3.31ppm；δC 49.0ppm)做内标，仪器为Bruker DRX-500光谱仪(Bruker BiospinAG,Germany)。
实施例2蛋白酪氨酸磷酸酶(PTP1B)活性实验
人源PTP1B活性片段(aa1-321)是通过大肠杆菌表达并纯化获得，PTP1B可特异性水解pNPP(对硝基苯磷酸二钠盐)的磷脂键，产物在405nm有很强光吸收，通过Spectra MAX340检测405nm处的光吸收强度的变化，计算得到反应初速度。
在96孔酶标板中加入100μL反应体系，具体反应体系为：50mM MOPS(3-吗啉丙磺酸),2％DMSO,2mM pNPP,30nM PTP1B,2mM DTT,1mM EDTA，pH6.5。检测不同浓度(20μg/mL，以2倍浓度梯度稀释)Xishacorene A对PTP1B活性的影响，同时设置以DMSO替代Xishacorene A的溶剂对照组。每个浓度设2个复孔。其数据处理以浓度的对数值对活性百分数作图，然后采用非线性回归拟和曲线，利用软件GraphPad Prism5公式log(inhibitor)vs.response--Variable slope计算得到IC50值。将已报道的化合物齐墩果酸作为阳性参照。
实验结果如表1所示。
表1 Xishacorene A对PTP1B活性的影响
该二萜类化合物Xishacorene A的PTP1B活性抑制测试表明，具有良好的PTP1B抑制活性，可以作为PTP1B抑制剂，并用于治疗糖尿病和/或肥胖症。

Claims (2)

1.式(Ⅰ)所示的二萜类化合物在制备治疗糖尿病和/或肥胖症的药物中的用途：
2.式(Ⅰ)所示的二萜类化合物在制备蛋白酪氨酸磷酸酶抑制剂中的用途：
CN201710456144.1A 2017-06-16 2017-06-16 一种二萜类化合物在制备治疗糖尿病或肥胖症的药物中的用途 Pending CN109125301A (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731277A (zh) * 2011-04-12 2012-10-17 中国科学院上海药物研究所 二萜类化合物豆荚甲素—己素、其制备方法及其在制备药物中的用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731277A (zh) * 2011-04-12 2012-10-17 中国科学院上海药物研究所 二萜类化合物豆荚甲素—己素、其制备方法及其在制备药物中的用途

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Application publication date: 20190104