CN103585616B - 二肽类似物的用途 - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明公开了二肽类似物的用途，特别是式（I）和（II）的化合物、立体异构体或其药学上可接受的盐在制药方面的用途。式（I）和式（II）所示化合物可能作为治疗和预防登革热病毒引起的疾病的药物，同时它们也可能成为治疗和预防其它黄病毒引起的疾病的药物，如黄热症、丙型肝炎、乙型脑炎、森林脑炎、由西尼罗河病毒感染引起的疾病或由HIV引起的爱滋病等。
Description
技术领域
本发明属于药物化学领域，具体涉及二肽类似物的化合物、立体异构体、或其药学上可接受的盐在药学上的应用。
背景技术
式（I）的化合物曾经被用于血管生成作用药物筛选的甲硫氨酸氨肽酶的底物（YingZhou,Xiao-Chuan Guo,Tian Yi,Tadashi Yoshimoto,Dehua Pei Analytical Biochemistry2000,280,159–165.）
而式（II）是式（I）的原料（Ying Zhou,Xiao-Chuan Guo,Tian Yi,Tadashi Yoshimoto,Dehua Pei Analytical Biochemistry2000,280,159–165.）
登革热疾病包括登革热(dengue fever，DF)、登革出血热(dengue hemorrhagic fever，DHF)和登革休克综合征(dengue shock syndrome，DSS)症状，它是由黄病毒科（flaviviridae）登革热病毒（dengue virus，DENV）感染引起的。登革热病传染主要在热带和亚热带地区，通过埃及伊蚊(Aedes aegypti)、白纹伊蚊(Aedes albopictus)和波利尼西亚伊蚊(Aedes polynesiensis)传播的，一般被具传染性的伊蚊(Aedes)叮咬之后3-14天出现登革热病症状(平均4-7天)。最早登革热疾病大流行的记录是在200多年前的亚洲、非洲、北美洲，现在登革热疾病已经在全球100多个国家发生过，据估计目前全球约有25亿人口受到登革热疾病的威胁，每年约有2.5万人死于登革热疾病。
在全球环境恶化和变暖等诸多因素影响下，登革热疫情近年有扩大的趋势，但目前没有有效的疫苗用于预防登革热疾病的发生和流行，也没有有效的抗登革热病毒的药物可用于临床治疗登革热疾病，现在临床治疗主要是渐进的支持疗法(intensive supportivetherapy)，其中维持体液平衡是主要手段。这些有限的手段无法应对登革热病毒感染引起的DHF和DSS有着较高的死亡率(～5%)的局面，所以对登革热病毒感染引起的登革热疾病的药物研究显得极为重要和迫切。
登革热病毒为单股正链RNA病毒，约含11000个碱基，共有4个血清型，即DENV-1,DENVV-2,DV-3和DV-4，其中DV-2毒力最强。登革热病毒基因组RNA可分为两部分：5’端1/4的顺序编码病毒的3个结构蛋白(C-capsid,prM-precursor membrane和E-envelope)，3’端3/4的顺序编码7个非结构蛋白(NS1,NS2,NS3,NS4A,NS4B和NS5)。虽然这些蛋白对于登革热病毒的生存都很重要，它们都可以作为抗登革热病毒药物靶标，但由于这些蛋白成熟依赖于NS3蛋白酶活性，有效抑制NS3蛋白酶活性可能达到降低或阻断登革热病毒复制和繁殖的目的，所以登革热病毒NS3是研究得最多也可能是最重要的登革热病毒的药物靶标（Aruna Sampath,R.Padmanabhan Antiviral Res.2009,81,6–15）。。研究表明，NS2B作为NS3蛋白酶的辅助因子对NS3发挥酶活性起着至关重要的作用，所以抑制剂对NS3酶活性抑制能力的研究使用的是NS3-NS2B复合物（Aruna Sampath,R.Padmanabhan AntiviralRes.2009,81,6–15）。。
登革热病毒所属的黄病毒家族(Flaviviridae family)有70多个病毒成员，其中研究的比较多也是危害较大的是黄热症(yellow fever virus)、西尼罗病毒(West Nile virus，WNV)、丙肝病毒(hepatitis C virus,HCV)、登革热病毒(dengue virus,DENV)等，由于它们在生命周期的许多方面是相似的，尤其是NS3-NS2B的功能上存在极大的相似性，所以在NS3蛋白酶药物研究过程中通常将它们相互联系在一起,这些化合物也可以用于预防和治疗登革热病毒之外的其它黄病毒引起的相关疾病，如黄热症、丙型肝炎、乙型脑炎、森林脑炎、西尼罗河病毒感染引起的疾病以及HIV引起的爱滋病等（Aruna Sampath,R.PadmanabhanAntiviral Res.2009,81,6–15）。
近年来对于黄热病毒NS3-NS2B的抑制剂研究一直是抗病毒药物的重点，最近也有一些环多肽类抑制剂（Shaoqiong Xu,Hua Li,Xiaoxia Shao,Chongxu Fan,Bryan Ericksen,Jinsong Liu,Chengwu Chi,Chunguang Wang J.Med.Chem.2012,55,6881-7.）和苯腙类抑制剂（Jing Deng,Ning Li,Hongchuan Liu,Zhili Zuo,Oi Wah Liew,Weijun Xu,Gang Chen,Xiankun Tong,Wei Tang,Jin Zhu,Jianping Zuo,Hualiang Jiang,Cai-Guang Yang,Jian Li,Weiliang Zhu J.Med.Chem.2012,55,6278-6293.）报道。
发明内容
本发明的目的是供式（I）和（II）的化合物、立体异构体或其药学上可接受的盐在制药方面的用途。
本发明的目的可以通过以下措施达到：
式（I）或（II）所示的化合物、异构体或其药学上可接受的盐在制备预防或治疗与登革热病毒NS3-NS2B蛋白酶抑制剂有关疾病的药物中的用途；
本发明进一步提供了式（I）或（II）所示的化合物、立体异构体或其药学上可接受的盐在制备预防或治疗登革热病毒NS3-NS2B蛋白酶抑制剂中的用途。
本发明特别是提供了式（I）或（II）所示的化合物、立体异构体或其药学上可接受的盐在登革热病毒引起的登革热疾病、登革出血热或登革休克综合症的药物中的用途，或者是在制备预防或治疗黄热症、丙型肝炎、乙型脑炎、森林脑炎、及由西尼罗河病毒感染引起的疾病或由HIV引起的爱滋病的药物中的用途；
本发明还公开了一种预防或治疗与登革热病毒NS3-NS2B蛋白酶抑制剂有关疾病的药物组合物，其特征在于该组合物中以式（I）或（II）所示的化合物、立体异构体或其药学上可接受的盐为活性成分之一。进一步的，该组合物中以式（I）或（II）所示的化合物、异构体或其药学上可接受的盐为活性成分，并辅以药学上可接受的辅料。
定义
构成本发明的一部分是药学上可接受的溶剂化物，可以使结晶水合物或者是与其它溶剂结晶物，如乙醇等。
构成本发明的一部分是药学上可接受的盐：包括本发明化合物和无机酸或有机酸反应形成的本发明化合物的常规无毒盐。例如，包括得自无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等的盐。
式（I）和式（II）的立体异构体是指脯氨酸（proline）的手性碳（星号表示）和甲硫氨酸（或称蛋氨酸，methionine）的手性碳（星号表示）所产生的立体异构体。
本发明的有益效果是发现了式（I）和式（II）所示化合物具有较好抑制登革热病毒蛋白酶NS2B-NS3酶活性的功能，它们可能作为治疗和预防登革热病毒引起的疾病的药物，同时它们也可能成为治疗和预防其它黄病毒引起的疾病的药物，如黄热症、丙型肝炎、乙型脑炎、森林脑炎、由西尼罗河病毒感染引起的疾病或由HIV引起的爱滋病等。
附图说明
图1是式（I）化合物抑制NS2B-NS3的Dixon作图。
图2是式（II）化合物抑制NS2B-NS3的Dixon作图。
图3是抑制常数Ki取值示意图。
具体实施方式
实施例1
构建好的NS3-NS2B融合蛋白表达质粒PET15b-CF40-Linker-NS3pro185（CF40是NS2B的亲水区核心序列1394-1440区间的40个氨基酸，Linker是Gly4-Ser-Gly4可以自由转动的序列，NS3pro185是NS3的N端1476-1660间185个氨基酸序列）由新加坡诺华热带疾病研究所Dr.Siew Phengsuozeg Lim提供（详见Jun Li,Siew Pheng Lim,David Beer,Viral Patel,Daying Wen,Christine Tumanut,David C.Tully,Jennifer A.Williams,Jan Jiricek,John P.Priestle,Jennifer L.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280(31),28766-28774.）。NS3-NS2B融合蛋白表达质粒PET15b-CF40-Gly-NS3pro185在大肠杆菌BL21(DE3)中的表达产物重组表达的蛋白酶可用通过组氨酸标签(His-tag)与Ni2＋亲和层析柱辅以其它层析方法进行纯化，纯化的蛋白酶具有正常的NS3酶活性（详见Jun Li,SiewPheng Lim,David Beer,Viral Patel,Daying Wen,Christine Tumanut,David C.Tully,JenniferA.Williams,Jan Jiricek,John P.Priestle,Jennifer L.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280(31),28766-28774和Shaoqiong Xu,Hua Li,Xiaoxia Shao,Chongxu Fan,Bryan Ericksen,Jinsong Liu,Chengwu Chi,Chunguang Wang J.Med.Chem.2012,55,6881-6887。）。
抑制剂活性测定的方法是灵敏高效的用荧光底物测定蛋白酶活性的方法，能保证通过抑制剂活性的测定对各种抑制剂进行有效筛选。基本酶学计算方法是通过2个或以上固定的底物浓度[S]下改变抑制剂[I]的浓度，利用Dixon作图法（M.Dixon Biochem.J.1953,55,170-171.）方程作图求抑制常数Ki，取值方法如图3所示。
筛选过程如下（参考Jun Li,Siew Pheng Lim,David Beer,Viral Patel,Daying Wen,Christine Tumanut,David C.Tully,Jennifer A.Williams,Jan Jiricek,John P.Priestle,JenniferL.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280(31),28766-28774和Shaoqiong Xu,Hua Li,Xiaoxia Shao,Chongxu Fan,Bryan Ericksen,Jinsong Liu,ChengwuChi,Chunguang Wang J.Med.Chem.2012,55,6881-6887。）：登革热蛋白酶NS2B-NS3孵育在37℃的缓冲液（50mM Tris-HCl,pH9.0,10mM NaCl,20%Glycerol,1mM CHAPS,0.04%NaN3）中，然后加入需要检测的抑制剂化合物并与酶孵育3分钟后，再加入蛋白酶NS2B-NS3的底物Benzoyl-Nle-Lys-Arg-Arg-AMC（终浓度为33μM和66μM），然后检测被酶NS2B-NS3分解的底物就是未被抑制剂抑制的剩余的NS2B-NS3的活力，分解形成的AMC荧光激发和发射波长分别为356nm和438nm。
式（I）和式（II）所示化合物的抑制常数Ki分别为4.86μM和10.5μM，作图分别如图1和图2。
Claims (5)
1.式(I)或(II)所示的化合物或其药学上可接受的盐在制备预防或治疗与登革热病毒蛋白酶NS3抑制剂有关疾病的药物中的用途；
2.根据权利要求1所述的用途，其特征在于所述与登革热病毒蛋白酶NS3抑制剂有关疾病为登革热病毒引起的登革热疾病。
3.根据权利要求1所述的用途，其特征在于所述与登革热病毒蛋白酶NS3抑制剂有关疾病为登革出血热或登革休克综合症。
4.式(I)或(II)所示的化合物或其药学上可接受的盐在制备登革热病毒蛋白酶NS3抑制剂中的用途；
5.式(I)或(II)所示的化合物或其药学上可接受的盐在制备预防或治疗登革热病毒引起的疾病的药物中的用途；
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