FDA批准抗血小板药Zontivity用于心梗和卒中高危患者

2014年5月美国FDA批准Zontivity（vorapaxar）用于心肌梗死、卒中或外周动脉疾病患者,以减少心梗、卒中、心血管相关的死亡和冠脉血管重建的风险。PAR-1是一种可被凝血酶激活的受体,而凝血酶是一种有效的血小板激活剂。Zontivity是一种首创的蛋白酶激活受体1拮抗剂,可以抑制凝血酶诱导的血小板激活,抑制血小板聚集。     

凝血酶受体拮抗剂的研究进展

血栓栓塞性疾病严重威胁人类健康,应用抗血小板药物是当前主要的治疗手段之一。研究证明,凝血酶受体(又称蛋白酶激活受体-1,PAR-1)被凝血酶激活后,可诱导血小板活化。此外,PAR-1主要参与病理性血栓的形成,对人体正常的止血过程影响很小。因此,PAR-1已成为抗血小板药物研发的新兴靶点。目前,已有多个PAR-1拮抗剂如vorapaxar、F16618、F16357、ML161、RWJ-58259、PZ-128已上市或进入临床研究。综述了PAR-1的结构和作用机制以及小分子拮抗剂和多肽类拮抗剂的研究进展。     

凝血酶受体拮抗剂在抗血栓方面的研究进展

20世纪90年代初克隆和发现的凝血酶受体(PAR-1)为研制抗血栓药物提供了一个新靶点,引起学术界和制药业的广泛关注。由于凝血酶受体的特殊活化机制,其自身相连的活化氮端与活化中心近在咫尺,只有结合力很高的小分子化合物才能有效地拮抗凝血酶受体。因此,多年来,只有少数化合物被发现具有较好的凝血酶受体拮抗活性,其中vorapaxar和atopaxar进入了临床试验。vorapaxar在Ⅲ期临床试验发现有显著疗效,但也有出血不良反应,尤其不适用于有中风史的患者。最近,vorapaxar与PAR-1结合的晶体结构已经发表。这些结果为设计和研制新一代凝血酶受体拮抗剂指出了优化的方向,提供了分子水平的结构信息。本文从药物化学角度综述近年来凝血酶受体拮抗剂的研究进展和现状,重点描述vorapaxar、atopaxar以及相关化合物和最新发表的PAR-1拮抗剂。     

蛋白酶激活受体-4拮抗剂的研究进展

蛋白酶激活受体-4(PAR-4)是一个由300个氨基酸经过7次跨膜形成的G蛋白偶联受体,它可通过与凝血酶的结合诱导血小板聚集,参与凝血过程。因此,PAR-4受体可以作为抗血小板药物的新靶点。近年来研究者发现了3种不同结构类型的小分子PAR-4受体拮抗剂,分别含有吲唑、吲哚和咪唑并噻二唑结构。对这几种拮抗剂的结构、药理活性等方面的研究进展进行综述。     

研究显示Schering-Plough的口服凝血酶受体拮抗剂达到主要终点

Schering-Plough公司关于新型口服凝血酶受体拈抗剂（TRA）SCH530348的Ⅱ期试验结果发表，显示此试验性抗血小板化合物达到安全性和耐受性的主要终点。对进行经皮冠脉介入（PCI）的患者，TRA与目前标准抗血小板治疗（阿司匹林和氯吡格雷）同用不增加心肌梗死溶栓（TIMI）的大出血和小出血。     

凝血酶蛋白酶激活受体-1作为转移性黑色素瘤治疗潜在靶点的研究进展

黑色素瘤由于转移性强,成为皮肤癌中死亡率最高的恶性肿瘤之一,目前没有有效的治疗方法。凝血酶蛋白酶激活受体-1(PAR-1)在黑色素瘤的发病过程中起到重要作用,PAR-1通过激活肿瘤细胞黏附和侵袭以及新生血管因子生成促进黑色素瘤转移。PAR-1有望成为治疗转移性黑色素瘤药物新靶点。     

沃拉帕沙的临床研究进展

沃拉帕沙为选择性、口服、强力、竞争性蛋白酶激活受体1(PAR-1)拮抗剂,对凝血酶诱导的血小板聚集有很强的抑制作用。沃拉帕沙口服后快速吸收,具有独特的药动学特性,半衰期长达7 d(159~311 h)。它主要经胆汁和胃肠道代谢和消除。2个针对急慢性冠状动脉粥样硬化患者的大型Ⅲ期临床试验结果表明,沃拉帕沙可以防止有心肌梗死病史、或者外周动脉疾病患者血栓性心血管病的发作,也可降低心肌梗死、中风和紧急冠脉血管重建患者的死亡率。     

抗血小板药物研究进展

近年来心脑血管疾病对人类健康已造成严重威胁,因而开发安全有效、价格低廉的抗血栓、抗血小板及抗凝血药已成当务之急。阿司匹林与氯吡格雷是目前抗血小板治疗的标准组合。但两药合用导致的出血发生率增加、以及日益受到关注的阿司匹林和氯吡格雷抵抗等问题,使得现有抗血小板治疗难以满足临床需要。本文从ADP受体抑制剂、凝血酶受体抑制剂、5-羟色胺受体抑制剂这四方面综述了近年来新的抗血小板药物的研究进展。     

SCH 530348开始关键性Ⅲ期临床试验

Schering—Plough公司开始了一项涉及3万例病人的抗血小板药SCH 530348（Ⅰ）关键性临床试验计划。它将包括两项Ⅲ期临床试验，观察这个口服抗凝血酶受体拮抗剂（它是这类药物中的第一个）治疗和预防急性冠脉综合征（ACS）病人和那些以前患过心肌梗死或卒中的病人，以及现患外周动脉病病人的心脏事件的疗效。     

Vorapaxar sulfate

<正>2014年5月8日由默沙东公司开发的vorapaxar sulfate被美国食品药品监督管理局(FDA)批准上市,其商品名为Zontivity。该药是一种蛋白酶激活受体-1(PAR-1)拮抗剂,适用于有心肌梗死或有外周动脉疾病史患者中血栓性心血管事件的减低[1]。     

Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.     

Thrombin receptor antagonism –the potential of antiplatelet medication SCH 530348

Importance of the field: Coronary artery disease is a leading cause of morbidity and mortality worldwide. Platelet activation and subsequent thrombus formation play a central role in disease progression and development of acute coronary syndromes (ACS). Despite widespread use of single and dual antiplatelet therapies in atherothrombotic disease, ischemic complications remain common. Therefore, the need exists for new antiplatelet agents that are more effective, but with acceptable safety profiles (i.e., do not increase risk of bleeding). Antiplatelet agents available at present are effective in blocking the cyclo-oxygenase, ADP-mediated and final common (IIb/IIIa receptor) pathways for platelet activation. Recently, there has been more interest in inhibition of the proteinase-activated receptor-1 (PAR-1), which blocks thrombin-mediated platelet activation.

Areas covered in this review: This review covers the pharmacology, pharmacokinetics and development of the new PAR₁ antagonist, SCH 530348 in a review of all publications relevant to the topic over the last 10 years. Phase II clinical trials indicate that addition of this agent to current antiplatelet regimens may provide additional antithrombotic protection without an increase in bleeding. Results of the ongoing Phase III trials, examining the use of SCH 530348 in patients with ACS and for secondary prevention of ischemic events are anxiously awaited.

What the reader will gain: The review is a summary of all pharmacologic properties and current clinical data available on the PAR1 antagonist SCH 530348. The readers will be introduced to its novel mechanism of action, advantages over current antiplatelet agents and potential future applications should ongoing clinical trials confirm its efficacy in reducing platelet activity.

Take home message: SCH 530348 is a new, orally administered antiplatelet agent that blocks the protease-activated thrombin receptor on the platelet. Early clinical data indicate that it is associated with a lower risk of bleeding. However, its efficacy in improving clinical outcomes in patients with coronary disease remains to be confirmed in ongoing Phase III clinical trials.     

Pharmacologic evaluation of SCH-39166, A-69024, NO-0756, and SCH-23390 in neonatal-6-OHDA-lesioned rats. Further evidence that self-mutilatory behavior induced by L-dopa is related to D1 dopamine receptors.

The purpose of the present investigation was to explore further the hypothesis that the self-injurious behavior induced by L-dihydroxyphenylalanine (L-DOPA) in neonatal-6-hydroxydopamine (OHDA)-lesioned rats is associated with an action on D1 dopamine receptors. This was accomplished by examining the behavioral responses induced by SKF-38393, quinpirole, and L-DOPA after treatment with the D1 antagonist SCH-23390 and three new pharmacologic agents, SCH-39166, NO-0756, and A-69024, reported to be D1 antagonists. All putative D1 antagonists were found to antagonize the action of SKF-38393 without reducing the increased locomotion and behavioral responses induced by quinpirole, consistent with an in vivo action on D1 receptors. The potency hierarchy of the compounds against the action of SKF-38393 on activity, from strongest to weakest, was: SCH-39166 equaled SCH-23390 and these were greater than NO-0756, which was greater than A-69024. All compounds were found to antagonize L-DOPA-induced self-mutilatory behavior (SMB) in neonatal-6-OHDA-lesioned rats in a dose-related manner. The potency hierarchy against this behavior, from strongest to weakest, was: SCH-23390, SCH-39166, NO-0756, and A-69024. The correlation between the ED50 for the ability of these drugs to antagonize SKF-38393-induced activity and their ability to reduce SMB by L-DOPA was greater than 0.99. In conclusion, the present findings provide additional evidence in vivo that NO-0756, SCH-39166, and A-69024 are selective D1 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of a novel thrombin receptor antagonist (SCH 530348) in human plasma: evaluation of Ultra Performance Liquid Chromatography™-tandem mass spectrometry for routine bioanalytical analysis

SCH 530348 is a safe and effective oral anti-platelet agent for patients with acute coronary syndrome. Clinical study results suggest that SCH 530348 dosage at 20 mg or 40 mg is feasible to achieve rapid maximum platelet inhibition following an acute coronary event or intervention procedure. To permit accurate determinations of circulating SCH 530348 in plasma following dosing, a method for measuring SCH 530348 concentrations in human plasma was validated using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The method utilized semi-automated 96-well protein precipitation with gradient chromatography using an ACQUITY™ UPLC BEH C₁₈ (2.1 mm × 50 mm, 1.7 μm) column. The retention time of SCH 530348 was approximately 1.5 min. This method was validated for routine quantitation of SCH 530348 over the concentration range of 1.00–1000 ng/mL. Inter-run accuracy based on mean percent theoretical for replicate quality control samples was better than 95.2%. Inter-run precision based on percent relative deviation for replicate quality control samples was ≤3.3%. SCH 530348 quality control samples were stable in human plasma for up to three freeze/thaw cycles, for at least 467 days when frozen at −20 °C and for at least 7 h when stored at room temperature. The lower limit of quantitation was 1.00 ng/mL for a 100 μL plasma aliquot.     

Inhibition of mu opioid-induced motor activity in the ventral pallidum by D1 receptor blockade

Microinjection of the mu opioid, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) into the ventral pallidum (VP) elicits a motor stimulant response. The coadministration of dopamine (DA) antagonists with DAMGO into the VP was used to determine the role of DA transmission in the motor response. The mixed D1/D2 antagonist, fluphenazine, was found to produce a partial reduction in DAMGO-induced motor activity. To evaluate the role of DA receptor subtypes, the D1 and D2 selective antagonists, SCH-23390 and raclopride, respectively, were coadministered with DAMGO into the VP. SCH-23390 was found to produce a dose-dependent reduction in both horizontal and vertical motor activity with a minimum effective dose of 0.3nmol/side. However, only a partial reduction in horizontal activity occurred with a dose of SCH-23390 as high as 6.0nmol/side. Raclopride was without effect at any dose examined, and an equimolar mixture of SCH-23390 and raclopride did not alter the minimum effective dose nor the maximum reduction in motor activity produced by SCH-23390 alone. It is concluded that stimulation of D1 receptors is permissive to the motor stimulant effect elicited by DAMGO in the VP.     

Neuroanatomical substrates mediating the aversive effects of D-1 dopamine receptor antagonists

An unbiased place preference conditioning procedure was used to examine the secondary reinforcing effects of selective D-1 dopamine (DA) receptor antagonists and the neuroanatomical substrates mediating these effects. Systemic administration of SCH-23390 or the non-benzazepine D-1 receptor antagonist A-69024 produced dose-related conditioned aversions for the drug-associated place. In contrast, the D-2 antagonists spiperone and (–)sulpiride were without effect. SCH-23390-induced place aversions were also observed after intracerebroventricular administration. The minimum dose producing this effect was significantly lower than that after systemic injection. Aversive effects were also observed after microinjection of SCH-23390 into the n. accumbens. In contrast, microinjections of this antagonist into the ventral tegmental area, caudate putamen or medial prefrontal cortex were without effect. These data confirm that the blockade of D-1 but not D-2 DA receptors induces aversive states. Furthermore, they suggest that D-1 receptors in the n. accumbens may play an important role in the regulation of non-drug induced affective states.     

The 'allosteric modulator' SCH-202676 disrupts G protein-coupled receptor function via sulphydryl-sensitive mechanisms

1. Previous studies suggest that the thiadiazole compound SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene)methanamine) acts as an allosteric modulator of a variety of structurally distinct G protein-coupled receptors (GPCRs). It was postulated that SCH-202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family. The molecular mechanisms of such a promiscuous action, however, remain obscure. 2. To clarify the mechanism of SCH-202676 action, we used the functional approach of [35S]GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [35S]GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi-family of G proteins. 3. We found that in the absence of dithiotreitol (DTT), SCH-202676 (10(-7)-10(-5) M) elicits nonspecific effects in the [35S]GTPgammaS-based G protein activation assays, thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor-mediated G protein activity. Such a nonspecific behaviour was fully reversed upon addition of DTT (1 mM), revealing thiol-based mechanism of action. 4. In routine incubations containing DTT, SCH-202676 had no effect on receptor-driven G protein activity, as assessed for adenosine A1, alpha2-adrenergic, cannabinoid CB1, lysophosphatidic acid LPA1, muscarinic M2/M4, purinergic P2Y12 or sphingosine 1-phosphate receptors, suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function. 5. 1H NMR analysis indicated that SCH-202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue. 6. We conclude that SCH-202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms.     

SCH-202676: An allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors

A novel thiadiazole compound, SCH-202676 (N-(2,3-diphenyl-1,2, 4-thiadiazol-5-(2H)-ylidene)methanamine), has been identified as an inhibitor of both agonist and antagonist binding to G protein-coupled receptors (GPCRs). SCH-202676 inhibited radioligand binding to a number of structurally distinct, heterologously expressed GPCRs, including the human mu-, delta-, and kappa-opioid, alpha- and beta-adrenergic, muscarinic M1 and M2, and dopaminergic D1 and D2 receptors, but not to the tyrosine kinase epidermal growth factor receptor. SCH-202676 had no direct effect on G protein activity as assessed by [35S]guanosine-5'-O-(gamma-thio)triphosphate binding to purified recombinant G(oalpha)- or G(betagamma)-stimulated ADP-ribosylation of G(oalpha) by pertussis toxin. In addition, SCH-202676 inhibited antagonist binding to the beta2-adrenergic receptor expressed in Escherichia coli, a system devoid of classical heterotrimeric G proteins. SCH-202676 inhibited radiolabeled agonist and antagonist binding to the alpha2a-adrenergic receptor with an IC50 value of 0.5 microM, decreased the Bmax value of the binding sites with a slight increase in the KD value, and inhibited agonist-induced activation of the receptor. The effects of SCH-202676 were reversible. Incubation of plasma membranes with 10 microM SCH-202676 did not alter subsequent radioligand binding to the alpha2a-adrenergic receptor and the dopaminergic D1 receptor. Taken together, our data suggest that SCH-202676 has the unique ability to allosterically regulate agonist and antagonist binding to GPCRs in a manner that is both selective and reversible. The scope of the data presented suggests this occurs by direct interaction with a structural motif common to a large number of GPCRs or by activation/inhibition of an unidentified accessory protein that regulates GPCR function.     

PAR-1 Inhibitors: A Novel Class of Antiplatelet Agents for the Treatment of Patients with Atherothrombosis

Stroke and myocardial infarction are leading causes of death and disability worldwide. Typically, these events are triggered by the rupture or erosion of "vulnerable" atherosclerotic plaque, a phenomenon termed atherothrombosis.Three platelet activation pathways are presumed to be particularly important in the genesis of atherothrombosis and are triggered by 1) cyclo-oxygenase (COX)-1 mediated thromboxane A2 (TXA2) synthesis and activation via the TXA2 receptor, 2) adenosine diphosphate (ADP) via the P2Y12 receptor, and 3) thrombin via the protease activated receptor (PAR)-1.Despite the efficacy of aspirin and of a growing family of P2Y12 receptor antagonists on the first 2 pathways, major cardiovascular events continue to occur in patients with coronary and cerebrovascular disease, suggesting that thrombin-mediated platelet activation may contribute to these adverse events.Recently, a novel class of antiplatelet agents able to inhibit thrombin-mediated platelet activation has been developed, PAR-1 inhibitors. In this chapter, we will discuss the rationale underlying the development of this novel class of agents focus on the two drugs in the most advanced stages of development: vorapaxar (SCH530348) and atopaxar (E5555).     

The effect of dopamine receptor blockade on motor behavior in Aplysia californica

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P<.001), siphon withdrawal (P<.05), and galloping following tail pinch (P<.01) compared to raclopride-injected or control animals. The data showed that blockade of receptors by SCH-23390, but not raclopride, produced significant changes in motor behavior in A. californica.