基于分子对接技术的血小板P2Y12受体拮抗剂研究现状

P2Y12受体是存在于血小板表面的一种G蛋白偶联受体,在血小板聚集过程中发挥重要作用.其受体拮抗剂是一类抑制血小板聚集的药物,临床上主要用于预防和治疗由血小板异常聚集所致血栓性心脑血管疾病.氯吡格雷即为一种P2Y12受体拮抗剂,是目前临床上首选的抗血小板聚集药物之一,但因存在“氯吡格雷抵抗”等缺陷,其疗效受到极大影响.因此,新型P2Y12受体拮抗剂类抗血小板聚集药物的研发备受关注.综述应用分子对接技术进行的血小板P2Y12受体及其拮抗剂研究的最新进展,包括P2Y12受体与配体的结合模式以及P2Y12受体拮抗剂的构效关系研究,为高效低毒的抗血小板聚集新药的开发提供参考.     

新型P2Y12受体拮抗剂抗血小板活性的影响因素研究进展

目的:综述新型P2Y12受体拮抗剂抗血小板活性的影响因素,为其临床合理用药提供参考。方法:以"P2Y12受体拮抗剂""氯吡格雷""普拉格雷""替格瑞洛""坎格瑞洛""抗血小板""抵抗""血小板反应性""影响因素""P2Y12-receptor inhibitor""Clopidogrel""Prasugrel""Ticagrelor""Cangrelor""Antiplatelet""Resistance""Platelet reactivity""Influence factor"等为关键词,组合查询2000年1月-2019年6月在中国知网、万方数据、Pub Med、Elservier、Springer Link等数据库中的相关文献,总结新型P2Y12受体拮抗剂抗血小板活性的影响因素。结果与结论:共检索到相关文献943篇,其中有效文献62篇。影响新型P2Y12受体拮抗剂抗血小板活性的因素有基因多态性、网织血小板水平、药物相互作用、合并症及服药方式等。CYP2C19、CYP4F2代谢型基因可能通过改变P2Y12受体拮抗剂的有效暴露量而影响其抗血小板活性;腺苷A2a受体基因型可通过影响腺苷与受体的结合效率影响其抗血小板活性。网织血小板水平对普拉格雷或替格瑞洛的抗血小板活性可能存在影响,而对坎格瑞洛的抗血小板活性没有影响。P2Y12受体拮抗剂间的相互转换、与阿片受体激动剂的联用可能影响P2Y12受体拮抗剂疗效;他汀类药物会影响P2Y12受体拮抗剂(如普拉格雷、替格瑞洛)的药动学,但并不影响其抗血小板活性。合并症如糖尿病、维他命D缺乏会削弱P2Y12受体拮抗剂的抗血小板活性;服药方式和服药时间等也会影响新型P2Y12受体拮抗剂的抗血小板活性。新型P2Y12受体拮抗剂疗效确切、不良反应小、临床使用广泛,但影响其活性的因素较多,且具体机制暂不明确,因此,后续可对其影响机制进行深入研究,以期为新型P2Y12受体拮抗剂的临床合理用药提供参考。     

氯吡格雷基因多态性在东亚人群中的研究进展

氯吡格雷是临床应用最广泛的抗血小板药物之一,但其临床疗效存在明显的个体差异,除临床因素外,遗传因素为另一个导致氯吡格雷疗效个体差异性的因素。氯吡格雷血小板高反应性(HTPR)相关基因的突变频率存在显著的种族差异,东亚人群的相关基因突变频率高于西方人群。目前研究表明,东亚人群发生氯吡格雷治疗期间HTPR的比例为20%~30%,高于西方人群,且CYP2C19*2和*3为HTPR的独立风险因素。通过增加氯吡格雷剂量,三联抗血小板治疗或换用新型P2Y12受体拮抗剂等策略可改善患者HTPR,并降低心血管事件的发生风险。     

影响氯吡格雷疗效的基因多态性研究进展

氯吡格雷是临床上常用的抗血小板药物,它通过不可逆地结合于P2Y12受体血小板上,从而减少了二磷酸腺苷介导的血小板聚集。虽然氯吡格雷疗效显著,但是存在明显的个体差异。了解可能引起氯吡格雷个体差异的因素从而提高氯吡格雷的疗效,降低不良心血管事件的发现,是目前临床工作者关心的问题。本文综述了影响氯吡格雷药动学和药效学的基因多态性,旨为氯吡格雷临床个体化给药提供一定的参考依据。     

新型血小板P2Y12受体拮抗药

抑制ADP诱导的血小板聚集的药物(如氯吡格雷)已成为目前心血管领域内最重要的抗血小板药物。但氯吡格雷起效较慢,抗血小板作用相对较弱,尚有一定的低反应者和无反应者。普拉格雷是一个较新的血小板P2Y12受体拮抗药。TRITON-TIMI 38研究表明普拉格雷可使主要终点发生率(心血管死亡、非致死性心肌梗死、非致死性卒中)降低19%,但使出血并发症增加。坎格雷洛,替格雷洛,依诺格雷是更新的血小板P2Y12受体拮抗药。     

吗啡对P2Y12受体拮抗剂药代及药效动力学的影响

吗啡联合P2Y12受体拮抗剂常用于急性心肌梗死患者的治疗。P2Y12受体拮抗剂能快速、强效抑制血小板活性,并降低再发栓塞风险,吗啡为心绞痛治疗的常规用药。既往有研究指出,吗啡能降低急性冠脉综合征患者氯吡格雷的血药浓度、减弱其抗血小板作用,并可能导致较差的预后。基于健康受试者和急性心肌梗死患者的随机试验也证实,吗啡与新型P2Y12受体拮抗剂替格瑞洛与普拉格雷同样存在类似的药物相互作用。尽管心肌梗死患者的治疗中仍存在吗啡合用P2Y12受体拮抗剂,然而,目前综述两药物相互作用的报道较少。因此,该文基于既往实验性、观察性和随机临床研究,概述吗啡与P2Y12受体拮抗剂之间的药物相互作用。     

抗血小板聚集药Brilinta

阿斯利康公司近期公布了一项名为PLATO研究的完整数据,宣布其开发的口服抗血小板新药——Brilinta（ticagrelor）比P2Y12受体拮抗剂氯吡格雷的作用更强、更快且更持久。噻吩并吡啶类化合物氯吡格雷能不可逆地阻断血小板上的二磷酸腺苷受体P2Y12,显著改善患者症状,是急性冠状动脉综合征（ACS）的一线治疗药物。但其也有一些缺点,如起效较慢、病人间个体差异较大;     

抗血小板药物替格瑞洛药代药效动力学及遗传药理学研究进展

替格瑞洛是2010年批准上市的抗血小板新药,属于新型环戊基三唑嘧啶类（CPTP）口服P2Y12受体拮抗剂。替格瑞洛口服后迅速吸收,中位达峰时间约1．5h。与已有P2Y12受体拮抗剂氯吡格雷和普拉格雷相比,替格瑞洛具有显著优势：无需代谢激活故起效迅速;与P2Y12受体呈可逆性结合,故停药后血小板功能恢复较快。此外,替格瑞洛可以通过抑制非血小板细胞表面的P2Y12受体从而产生其他药理学作用。替格瑞洛的药动学特征不受年龄、性别、饮食以及对氯吡格雷反应性的影响。替格瑞洛主要经CYP3A4代谢,可迅速产生血药浓度依赖的血小板抑制作用,且对氯吡格雷抵抗的患者同样有效。更重要的是,替格瑞洛的抗血小板作用不受具有多态性的药物转运体（ABCBl）和代谢酶（CYP2C19）基因型的影响。本文主要概述替格瑞洛药动学、药效学以及遗传药理学方面的研究进展。     

影响氯吡格雷疗效的因素及其对策研究

目的:为提高氯吡格雷的疗效,减少心血管不良事件的发生提供参考。方法:参考国内外关于氯吡格雷的疗效研究的相关文献资料,进行汇总分析。结果:氯吡格雷是前体药物,需要体内CYP2C19和CYP3A酶的活化,这两种酶在患者体内存在差异,从而会影响氯吡格雷的疗效;患者的联合用药所引起的药物之间的相互作用,也会影响氯吡格雷的疗效;患者自身的性别、疾病、体质量等都会影响氯吡格雷的疗效。结论:克服氯吡格雷疗效的差异,可通过慎重选择联用的药物、适当增加氯吡格雷的剂量,联合使用抗血小板药、选用新型的血小板P2Y12受体拮抗药等措施来实现。     

新型抗血小板聚集药物——替格瑞洛的研究进展

目的:为临床合理使用抗血小板聚集药物替格瑞洛提供参考。方法:归纳和整理近几年国内外有关替格瑞洛的文献报道和临床研究,对替格瑞洛药动学、药效学、安全性等方面的研究进展进行综述。结果:替格瑞洛为新型环戊基三唑嘧啶类药物,通过可逆性与血小板表面P2Y12受体结合抑制其与二磷酸腺苷结合,发挥抗血小板聚集作用。与氯吡格雷相比,具有起效迅速、停药后血小板功能恢复较快、有效降低心血管不良事件的发生等优势,同时不增加严重出血风险,具有很好的耐受性与安全性,且具有长期成本-效果优势。结论:替格瑞洛是一个很有潜力的新型血小板表面P2Y12受体拮抗药,在急性冠脉综合征治疗中优于氯吡格雷。     

ADP receptors: inhibitory strategies for antiplatelet therapy

The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y(1) and P2Y(12)) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y(12) ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y(12) antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y(12) antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y(1), are under development and may prove to be effective antithrombotic agents.     

ADP receptors--targets for developing antithrombotic agents

Platelet P2 receptors--P2Y1, P2Y12, and P2X1--constitute the means by which adenine nucleotides can activate platelets. Coactivation of the Galphaq-coupled P2Y1 and Galphai2-coupled P2Y12 receptors is necessary for ADP-mediated platelet activation, which forms the basis of using P2 antagonists as antithrombotic drugs. P2Y1 receptor antagonists inhibit platelet activation, while P2Y1 knockout mice show longer bleeding times than normal mice but few other problems; however, its ubiquitous expression in other tissues renders P2Y1 questionable as an antithrombotic target. The P2Y12 receptor is expressed nearly exclusively in platelets and brain, making it an attractive antithrombotic target. Antagonists for the P2Y12 receptor have been developed that either require metabolic activation to covalently inhibit P2Y12 and are irreversible, or simply are competitive in nature and thus reversible. Ticlopidine and clopidogrel are irreversible P2Y12 antagonists and have been repeatedly proven as clinical antithrombotic agents. In addition, a recently reported P2Y12 antagonist, CS-747, shows promise as a future antithrombotic drug. The AR-C series of compounds represent reversible P2Y12 antagonists and have been used extensively to characterize the function of P2Y12 in platelets. Clinical studies show that AR-C69931MX is as effective as clopidogrel; furthermore, the combination of AR-C69931MX (cangrelor) and clopidogrel confers greater antagonism of P2Y12 than either antagonist alone. The P2X1 receptor is a calcium channel that functions to potentiate agonist-induced platelet shape change, and its inhibition or loss has little if any effect on hemostasis. A combination of P2Y1 and P2Y12 antagonists may represent an additional course of antithrombotic treatment.     

Biology and pharmacology of the platelet P2Y12 receptor

Platelets possess two receptors for ADP, P2Y(1) and P2Y(12). ADP is released from platelet dense granules upon platelet activation by numerous agonists and thereby amplifies platelet responses regardless of the initial stimulus. The P2Y(1) receptor is one of many platelet receptors coupled to Gq and initiates ADP-induced activation. The P2Y(12) receptor on the other hand is linked to Gi and plays a special role in the amplification of platelet activation initiated by numerous other pathways. Platelet activation leads to a range of responses that play a critical role in arterial thrombosis and the inflammatory responses associated with this, including platelet aggregation, dense and alpha granule secretion and procoagulant activity. P2Y(12) receptor activation yields powerful amplification of these processes such that P2Y(12) receptor antagonists may have dramatic inhibitory effects on platelet function regardless of the activating stimuli. This phenomenon, coupled with the restricted distribution of the P2Y(12) receptor in humans, makes the receptor an ideal target for pharmaceutical therapy. This has already been established by the therapeutic success of clopidogrel, which acts, via an active metabolite, on this receptor. However, current therapeutic regimens of clopidogrel yield variable and incomplete P2Y(12) receptor blockade and more effective strategies to block P2Y(12) receptor activation offer the potential of greater clinical efficacy.     

Ticagrelor: a P2Y12 antagonist for use in acute coronary syndromes

Agents that inhibit platelet function are used routinely in the treatment and prevention of acute coronary syndromes. The main antiplatelet treatments used combine aspirin with one of the thienopyridine P2Y(12) antagonists, either clopidogrel or prasugrel. By blocking the synthesis of thromboxane A(2) in platelets and by blocking the effects of ADP, respectively, these agents reduce platelet activity, platelet aggregation and thrombus formation. Ticagrelor (marketed by AstraZeneca as Brilinta? in the USA, and as Brilique(?) or Possia(?) in Europe) is a cyclopentyl-triazolo-pyrimidine, a new chemical class of P2Y(12) antagonist that is now approved for use in the wide spectrum of acute coronary syndromes. In this article we provide an overview of ticagrelor. We discuss the differences in mode of action compared with other P2Y(12) antagonists, examine its pharmacodynamic, pharmacokinetic and safety profile, and summarize the various clinical trials that have provided information on its efficacy in combination with aspirin. Ticagrelor appears to overcome some of the difficulties that have been encountered with other antiplatelet treatments, clopidogrel in particular.     

ADP Receptor Antagonism

ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y(12) receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y(12) receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y(12) receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y(12) receptor antagonists - such as prasugrel, ticagrelor (AZD 6140) and cangrelor - will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y(12) receptor antagonism and the projected developments in this field.     

Pharmacokinetic,pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current ‘gold standard’ antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.     

Assessment of VerifyNow P2Y12 assay accuracy in evaluating clopidogrel-induced platelet inhibition

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from -142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from -49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.     

Prasugrel

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.     

P2Y receptor antagonists in thrombosis

The dual role of P2Y1 and P2Y12 receptors in platelet aggregation by ADP has been firmly established, based on the action of selective inhibitors, gene targeting in mice and human genetic evidence. Both of these receptor subtypes constitute targets for antithrombotic agents, and compounds with a dual action might also be of interest. However, the agents currently on the market (ticlopidine and clopidogrel), or known to be in development (cangrelor, AZD-6140 and prasugrel), all target the P2Y12 receptor. The thienopyridines (ticlopidine, clopidogrel and prasugrel) irreversibly inactivate the P2Y12 receptor via the covalent binding of an active metabolite generated in the liver, while the other compounds are competitive antagonists. Cangrelor, an ATP derivative, is suitable for intravenous perfusion, whereas AZD-6140 is in clinical development as an orally active agent.     

Efficacy and safety of ticagrelor in patients with acute coronary syndrome: A meta‐analysis of randomized controlled trials

Acute coronary syndrome (ACS) is a dangerous and urgent clinical pattern of coronary artery disease. Aspirin and adenosine diphosphate P2Y₁₂ receptor antagonists are the standard dual anti‐platelet therapy for patients with ACS. Ticagrelor is a new oral antagonist of the adenosine diphosphate P2Y₁₂ receptor. Randomized controlled trials (RCTs) have evaluated the efficacy and safety of ticagrelor compared to clopidogrel or prasugrel in patients with ACS, obtaining conflicting results. Thus, we conducted a meta‐analysis of these RCTs to determine the efficacy and safety of ticagrelor in patients with ACS. Results of the meta‐analysis indicate that ticagrelor decreased the risk of major adverse cardiovascular events (MACE) and all‐cause death, but increased the risk of bleeding events. In Asiatic patients, analysis indicates that ticagrelor did not decrease the risk of MACE and all‐cause death, while increasing the risk of bleeding events. Together, this meta‐analysis suggests that ticagrelor was more effective, but less safe than clopidogrel and prasugrel in patients with ACS. Subgroup analysis indicates that ticagrelor was not more effective, although less safe than clopidogrel in Asiatic patients, thus more evidence is needed to further evaluate the efficacy and safety of ticagrelor in Asiatic patients.