噻吩并吡啶类衍生物的设计、合成、活性评价及其药效团模型
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摘要
目前,随着生活水平的不断提高和高脂肪类食物在饮食比例中的增加,心脑血管疾病己逐渐成为当今世界人口死亡的主要原因。在已经明确的发病机理中血栓形成被认为是此类疾病及动脉粥样硬化相关疾病的主要并发症和致死原因。临床治疗血栓最有效的是噻吩并吡啶类P2Y_(12)受体拮抗剂,但是已经上市的药物都存在一定的不足,因此研制新一代的噻吩并吡啶类拮抗剂是新药研究的迫切任务。
通过对已上市的及文献报道的噻吩并吡啶类化合物的分析研究,从临床一线用药氯吡格雷的结构特性出发,保留噻吩并吡啶母核,通过电子等排等药物设计方法,设计了七类新型的噻吩并吡啶类衍生物237个。噻吩并吡啶类药物的受体P2Y_(12)属于G蛋白偶联受体,其实验性三维结构至今未获得。本文通过同源模建的方法构建了其三维结构,研究了该受体与其配体的相互作用方式,并以此作为虚拟筛选的工具,从设计的237个化合物中挑选出115个化合物进入合成阶段。最终成功合成了110个化合物,并进行了大鼠体内抑制血小板聚集活性测试,研究了初步构效关系。化合物C1、C12、C13、D1、E1、F7、F8、F18、G28、G34、G49具有很好的抗血小板活性,随后又对这11个化合物进行了大鼠抗血栓药理活性研究,证实了这些化合物确实具有通过抑制血小板聚集而起到抗血栓的作用。我们认为这11个化合物是很有药用研究前途的化合物。
为了进一步了解噻吩并吡啶类化合物与其受体P2Y_(12)的三维空间结合方式,以及为今后合理设计新的该类衍生物提供理论指导,选择活性最高的11个化合物进行药效团模型研究,为进一步的药物设计、结构优化和虚拟筛选提供了理论依据。
As people's living standard keeps on going up and the ratio of high-fat food in diets increased, cardiovascular disease (CVD) is rapidly emerging as the most important cause of mortality in the whole world. Thrombosis is considered to be the major complication and reason of causing death of CVD and atherosclerosis in known etiopathogenesis.Thienopyridines, antagonists of the platelet P2Y_(12) receptor, are the most effective drugs to prevent thrombus in clinical. Because of a number of limitations associated with drugs in the market novel antiplatelet thienopyridines are under research.
Structure of clopidogrel was determined to be the initial structure and the thienopyridine mother nucleus was kept by the study of drugs in the market and reported thienopyridines. Seven novel classes of thienopyridine derivatives (237 in total) were designed by the method of isostere and so on. P2Y_(12), receptor of thienopyridines belongs to G-protein-coupled receptor, its experimental 3D structure has not been got yet. In this paper, its 3D structure was modelled by homology modelling and the receptor-ligand interaction was predicted. 115 compounds were selected to be synthesized from designed 237 compounds by virtual screening using the modelled complex. Finally, 110 compounds were succeedly synthesized, their in vivo antiplatelet aggregation activities were evaluated and initial structure-activity relationship was studied. Compounds C1, C12, C13, D1, E1, F7, F8, F18, G28, G34 and G49 exhibited more potent inhibitory activity than other compounds synthesized and their antithrombotic effect was also evaluated. These 11 compounds were confirmed to have antithrombotic effect by inhibition of platelet aggregation. We think these 11 compounds have the potential to be drugs.
To study the 3D bind mode of thienopyridine and its P2Y_(12) receptor further and produce theoretical guide for designing novel derivatives, 11 compounds with highest activity were selected to construct pharmacophore models. These models will produce theoretical bases for drug design, strcture optimization and virtual screening.
通过对已上市的及文献报道的噻吩并吡啶类化合物的分析研究,从临床一线用药氯吡格雷的结构特性出发,保留噻吩并吡啶母核,通过电子等排等药物设计方法,设计了七类新型的噻吩并吡啶类衍生物237个。噻吩并吡啶类药物的受体P2Y_(12)属于G蛋白偶联受体,其实验性三维结构至今未获得。本文通过同源模建的方法构建了其三维结构,研究了该受体与其配体的相互作用方式,并以此作为虚拟筛选的工具,从设计的237个化合物中挑选出115个化合物进入合成阶段。最终成功合成了110个化合物,并进行了大鼠体内抑制血小板聚集活性测试,研究了初步构效关系。化合物C1、C12、C13、D1、E1、F7、F8、F18、G28、G34、G49具有很好的抗血小板活性,随后又对这11个化合物进行了大鼠抗血栓药理活性研究,证实了这些化合物确实具有通过抑制血小板聚集而起到抗血栓的作用。我们认为这11个化合物是很有药用研究前途的化合物。
为了进一步了解噻吩并吡啶类化合物与其受体P2Y_(12)的三维空间结合方式,以及为今后合理设计新的该类衍生物提供理论指导,选择活性最高的11个化合物进行药效团模型研究,为进一步的药物设计、结构优化和虚拟筛选提供了理论依据。
As people's living standard keeps on going up and the ratio of high-fat food in diets increased, cardiovascular disease (CVD) is rapidly emerging as the most important cause of mortality in the whole world. Thrombosis is considered to be the major complication and reason of causing death of CVD and atherosclerosis in known etiopathogenesis.Thienopyridines, antagonists of the platelet P2Y_(12) receptor, are the most effective drugs to prevent thrombus in clinical. Because of a number of limitations associated with drugs in the market novel antiplatelet thienopyridines are under research.
Structure of clopidogrel was determined to be the initial structure and the thienopyridine mother nucleus was kept by the study of drugs in the market and reported thienopyridines. Seven novel classes of thienopyridine derivatives (237 in total) were designed by the method of isostere and so on. P2Y_(12), receptor of thienopyridines belongs to G-protein-coupled receptor, its experimental 3D structure has not been got yet. In this paper, its 3D structure was modelled by homology modelling and the receptor-ligand interaction was predicted. 115 compounds were selected to be synthesized from designed 237 compounds by virtual screening using the modelled complex. Finally, 110 compounds were succeedly synthesized, their in vivo antiplatelet aggregation activities were evaluated and initial structure-activity relationship was studied. Compounds C1, C12, C13, D1, E1, F7, F8, F18, G28, G34 and G49 exhibited more potent inhibitory activity than other compounds synthesized and their antithrombotic effect was also evaluated. These 11 compounds were confirmed to have antithrombotic effect by inhibition of platelet aggregation. We think these 11 compounds have the potential to be drugs.
To study the 3D bind mode of thienopyridine and its P2Y_(12) receptor further and produce theoretical guide for designing novel derivatives, 11 compounds with highest activity were selected to construct pharmacophore models. These models will produce theoretical bases for drug design, strcture optimization and virtual screening.
引文
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[2] Ghaffar A, Reddy KS, Singhi M, Burden of non-communicable diseases in South Asia, BMJ, 2004, 328:807~ 810
[3] Karthikeyan G, Xavier D, Prabhakaran D, et al, Perspectives on the management of coronary artery disease in India, Heart, 2007, 93:1334~1338
[4] Popkin BM, Horton S, Kim S, et al, Trends in diet, nutritional status, and diet-related noncommunicable diseases in China and India: the economic costs of the nutrition transition, Nutr Rev, 2001, 59(12):379~390
[5] Xu C, Yang X, Zu S, et al, Association between serum lipids, blood pressure, and simple anthropometric measures in an adult Chinese population, Arch Med Res, 2008, 39(6):610~617
[6]武忠弼,病理学,北京:人民卫生出版社,1996,166
[7]李家增,血栓形成机制,临床内科杂志,2004,21(12):793~795
[8] Maraganore JM, The arterial thrombotic process and emerging drugs for its control, Tex Heart Inst J, 1993, 20(1):43~47
[9] Dewerchin M, Vandamme AM, Holvoet P, Thrombolytic and pharmacokinetic properties of arecombinant chimeric plasminogen activator consisting of a fibrin fragment D–dimer specific humanized monoclonal antibody and a truncated single–chain urokinase, Thromb Haemost, 1992, 68 (2):170~179
[10] Kruithof EKO, Nicolosa G, Bachmann F, Plasminogen activator inhibitor l: development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation, Blood, 1987, 70:1645~1653
[11]王鸿利,防栓和溶栓治疗实验室监测的参考意见,中华血液学杂志,1995, 16:498~499
[12]何晓红,滕利荣,孟庆繁,刘兰英,治疗血栓药物的研究进展,中国药学杂志,2005,40(4):248~251
[13]昝云红,孙茂盛,啤酒酵母生产的重组水蛭素的纯化及脱色,中国生物化学与分子生物学报,1999,15(5):780
[14]刘泽霖,贺天林,李天增,血栓性疾病的诊断与治疗,北京:人民卫生出版社,2000,3~25
[15] Mustard JF, The Gordon Wilson lecture: function of blood platelets and their role in thrombosis, Trans Am Clin Climatol Assoc, 1976, 87: 104~127
[16] Tan, HC, Platelet glycoprotein II b/ IIIa receptor antagonist: a new breakthrough in cardiology, Med Prog, 2000, 27(1):31~35
[17]李家增,贺石林,王鸿利,血栓学,上海:上海科学出版社,1998,322~336
[18]陈凌,郭若冰,戴军,氯吡格雷在缺血性心血管疾病防治中的作用,中国新药杂志,2000,9(10):718~722
[19] Smith EF 3rd, Thromboxane A2 in cardiovascular and renal disorders: is there a defined role for thromboxane receptor antagonist or thromboxane synthase inhibitors, Eicosanoids, 1989, 2(4):199~200
[20] Patrono C, Ciabtioni G, Patrignari D, et al, Clinical pharmacology of platelet cyclooxygenase inhibition, Circulation, 1985, 72:1177~1184
[21] Sheth SB, Colman RW, Platelet cAMP and cGMP phosphodiesterases, Platelets, 1994, 5:61~67
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