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。     

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。     

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。     

以血管紧张素受体为靶点的药物研究进展

血管紧张素Ⅱ受体共有4种亚型（ATI、AT2、AT3和AT4）.血管紧张素Ⅱ受体拈抗剂是临床上常用的高血压治疗药物,以ATl受体拮抗剂和AT2受体拮抗剂应用较多。近年来,随着对血管紧张素Ⅱ受体拮抗剂研究的深入,涌现出诸多具有良好药理活性的选择性ATl受体拮抗剂、双重作用靶点的非选择性ATl受体拮抗剂和选择性AT2受体拮抗剂。本文对近年来报道的血管紧张素Ⅱ受体拮抗剂进行简要综述。     

离子通道型嘌呤受体P2X4在中枢神经系统中的作用及其作为神经系统疾病干预靶标的前景

ATP除了作为细胞内能量来源物质,也可充当细胞外信号分子激活离子通道型的嘌呤受体P2X受体和G蛋白偶联受体型的P2Y受体。P2X4亚型是一类在中枢神经系统(CNS)广泛表达的P2X受体,通过感受胞外ATP的刺激而参与CNS生理过程,包括慢性痛、乙醇滥用、癫痫、阿尔茨海默病、帕金森病和卒中缺血等。因此,靶向P2X4受体的小分子拮抗剂或增强剂因为其药用前景而受到广泛关注。本文总结了P2X4受体在CNS中相关研究的进展情况,概述了近年来新发现的P2X4受体高选择性拮抗剂。     

小分子趋化因子受体4拮抗剂研究进展

CC类人类趋化因子受体4(CCR4)是趋化因子家族中具有7个跨膜结构的G蛋白偶联受体。CCR4受体与自身免疫性疾病、哮喘、特应性皮炎等多种疾病的形成和发展有关,可成为这些疾病新的治疗靶点,受到越来越多学者的关注。CCR4拮抗剂的研究成为研发治疗上述疾病药物新热点。本文对近年来小分子CCR4拮抗剂的研究进展进行综述。     

组胺受体H_1和H_4在过敏性炎症中的作用:新型抗组胺药的研究

组胺在过敏性炎症中起关键性作用,长期以来人们认为组胺释放引起的炎性反应是由H1受体介导的。H1受体拮抗剂也称为抗组胺药,用于治疗过敏性反应已很多年。但是在哮喘和慢性瘙痒症的病理状态下组胺的重要性可能被低估。已证明组胺的确在炎症和免疫调节疾病中起作用,特别是H4受体的发现及其在多种免疫和炎性细胞中的表达,提示应重新评价组胺的作用,预示新型H4受体拮抗剂将被发现,且H1,H4受体拮抗剂在许多炎性反应靶标上可能有协同作用。     

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。     

5-HT4受体拮抗剂哌波色罗的合成

目的合成5-HT4受体拮抗剂哌波色罗。方法以吲哚-3-羧酸甲酯为原料,在NBS、三乙胺作用下,与3-氯-1-丙醇反应,再经环合、胺解、成盐等反应,合成哌波色罗。结果与结论实验总收率为43%,其结构经熔点、氢谱、质谱测试确证。该方法合成工艺简单,易操作,收率高,成本低。     

蛋白酶激活受体-1在肺纤维化大鼠肺组织中的表达

目的探讨在博莱霉素所致大鼠肺纤维化模型肺组织中蛋白酶激活受体-1的表达。方法将体重180-250g的SD清洁级雄性大鼠48只,按完全随机方法分为对照组及博莱霉素(BLM)组,BLM组大鼠气管内注入0.9-1.25ml博莱霉素A5(BLMA5,5mg/kg),对照组在同样条件下向气管内注入等量的生理盐水。两组动物于气管灌注后第7、14、28、40d分别随机处死6只。组化方法检测肺组织PAR-1的表达;Masson染色检测肺组织纤维化,按Ashcroft评分法,评估肺纤维化的严重程度,结果(1)对照组无明显胶原沉积,BLM组随着时间的延长,可见明显胶原沉积,BLM组/对照组两组在第7、14、28、40d肺间质纤维化Ashcroft评分分别为24±3.72/3±0.63、46.4±4.09/4±0.63、69.3±3.78/3±1.41、64.5±5.96/3±1.67,两组有显著性差异(P﹤0.05)。(2)BLM组/对照组两组在第7、14、28、40d平均每高倍镜视野肺组织PAR-1阳性细胞数分别为:9.93±1.47/2.5±1.52、16.67±2.16/1.83±1.17、17.67±2.16/2.17±0.75、16.0±2.28/2.17±1.17。BLM组各时间点肺组织PAR-1阳性细胞数较正常对照组增多,两组具有显著统计学差异(P﹤0.05)。(3)肺间质纤维化程度与PAR-1阳性细胞数呈正相关(r=0.76)。结论博莱霉素所致大鼠肺纤维化模型肺组织中蛋白酶激活受体-1的表达增强;蛋白酶激活受体-1的表达可能在博来霉素所致肺纤维化中其重要作用。     

PAR-1622 is a selective peroxisome proliferator-activated receptor γ partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention

Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARγ. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARγ with an EC₅₀ of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARδ. PAR-1622 was 56 folds more selective for human PPARγ than for human PPARα (EC₅₀, 2304 nM), which means that it is a selective partial activator of PPARγ. PAR-1622 also showed a partial activator against mouse PPARγ with an EC₅₀ of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARγ partial agonist in clinical stage, also was a partial activator against human PPARγ with an EC₅₀ of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARγ and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.     

Thrombin promotes airway remodeling via protease-activated receptor-1 and transforming growth factor-β1 in ovalbumin-allergic rats

Abstract

Background: Protease-activated receptor-1 (PAR-1) is widely distributed in platelets and involved in coagulation cascade activated by thrombin. In this study, we intend to explore the role of PAR-1 in the process of thrombin-inducing transforming growth factor-β1 (TGF-β1) to promote airway remodeling in ovalbumin (OVA)-allergic rats.

Materials and methods: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06 varied for different groups. We evaluated the bronchoalveolar lavage fluid (BALF) concentration of thrombin in these groups. The protein and gene expression of PAR-1 was assessed and the expression of TGF-β1 was also detected.

Results: The PAR-1 mRNA level and the protein level were higher in the airway of asthmatic rats than those of normal rats, and were significantly increased by thrombin treatment but decreased by thrombin-inhibitor treatment. Airway remodeling was strengthened by thrombin but weakened by thrombin inhibitor and PAR-1 antagonist. Expression of TGF-β1 protein in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and PAR-1 antagonist treatment.

Conclusion: The expression of PAR-1 is regulated by thrombin that induces the expression of TGF-β1 to promote airway remodeling via PAR-1 in OVA-allergic rats.     

Suppression by protease-activated receptor-2 activation of gastric acid secretion in rats

Activation of protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, induces neurally mediated gastric mucus secretion accompanied by mucosal cytoprotection. In the present study, we investigated whether PAR-2 could modulate gastric acid secretion in rats. Messenger RNAs for PAR-2 and PAR-1 were detected in the gastric mucosa and smooth muscle. The PAR-2-activating peptide SLIGRL-NH(2), but not the inactive control peptide, when administered i.v., strongly suppressed gastric acid secretion in response to carbachol, pentagastrin or 2-deoxy-D-glucose in the rats with a pylorus ligation. The PAR-2-mediated suppression of acid secretion was resistant to cyclooxygenase inhibition or ablation of sensory neurons by capsaicin. Our results provide novel evidence that in addition to stimulating neurally mediated mucus secretion, activation of PAR-2 suppresses gastric acid secretion independently of prostanoid production or sensory neurons. These dual actions of PAR-2 would result in gastric mucosal cytoprotection.     

Protease-activated receptor-2-mediated contraction of urinary bladder is enhanced in cyclophosphamide-treated rats

Protease-activated receptor-2 (PAR-2) is activated by serine proteases, such as trypsin and mast cell tryptase. Recently, we have shown that activators of PAR-2 contract the rat urinary bladder mainly by stimulating release of prostaglandins (PGs) from the mucosal layer. In the present study, we investigated how the PAR-2-mediated responses are altered in rats with cyclophosphamide (CYP)-induced cystitis. The contractile responses to trypsin and PAR-2 activating peptide (PAR-2 AP; SLIGRL-NH₂) in the urinary bladders were augmented by treatment of rats with CYP. The contractile effects of these PAR-2 activators on the smooth muscles of the urinary bladder were also potentiated after induction of cystitis by CYP. On the other hand, CYP-induced cystitis significantly attenuated contractions produced by PGE₂ in the smooth muscles of the urinary bladder. The PAR-2-mediated contractions were significantly prevented by indomethacin or NS-398, an inhibitor of cyclooxygenase-2. Both trypsin and PAR-2 AP increased the release of PGE₂ from the urinary bladder mucosa and smooth muscle. CYP-induced cystitis enhanced the PAR-2 activators-induced PGE₂ releases from the urinary mucosa without affecting those from the smooth muscle of the urinary bladder. The PGE₂ releases were prevented by indomethacin or NS-398. The mRNAs for PAR-2 in the urinary bladder mucosa and smooth muscle preparations were not altered in CYP-induced cystitis. These results suggest that PAR-2-mediated responses were enhanced in bladders from CYP-treated rats. The enhancement of PAR-2-mediated contraction might be ascribed to the increased production of PGs and the altered sensitivity of smooth muscle to PAR-2 activators.     

Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar

相似文献   

Endothelium-dependent and -independent responses to protease-activated receptor-2 (PAR-2) activation in mouse isolated renal arteries

Protease-activated receptors (PARs) are receptors which require proteolytic cleavage to be self-activated by newly exposed N-terminal `tethered ligands'', and hence serve as sensors for protelytic enzymes. While both the thrombin receptor (PAR-1) and PAR-2 (activated by tryptic enzymes) have been shown to mediate endothelium-dependent vasorelaxation, only PAR-1 has been shown to cause direct vascular smooth muscle contraction. In this study, we report that trypsin and the PAR-2 selective peptide ligand SLIGRL-NH₂ not only caused endothelium-dependent relaxation of mouse renal arteries but also direct smooth muscle contraction if endothelial nitric oxide synthase was inhibited or if the endothelium was removed.     

Multiple roles for protease-activated receptor-2 in gastric mucosa

Protease-activated receptor-2 (PAR-2), a G-protein-coupled receptor, is activated by proteolytic unmasking of the N-terminal cryptic tethered ligand. In gastric mucosa, activation of PAR-2 expressed by sensory neurons triggers release of CGRP and tachykinins, leading to mucus secretion via activation of CGRP₁ and NK₂ receptors, respectively. The PAR-2 agonist reveals mucosal cytoprotective effects in several gastric injury models. Further, PAR-2 activation inhibits gastric acid secretion, independently of sensory neurons or prostanoid formation. The PAR-2 agonist also induces increase in gastric mucosal blood flow, an effect being independent of endogenous CGRP or NO. Endothelium-derived hyperpolarizing factor (EDHF) appears to be involved in the PAR-2-mediated enhancement of mucosal blood flow. In contrast, mucosal chief cells are abundant in immunoreactive PAR-2, and PAR-2 stimulation triggers pepsinogen secretion. Taken together, primarily, PAR-2 plays protective roles in gastric mucosa through multiple mechanisms. Considering PAR-2-mediated pepsinogen secretion, PAR-2 might function as a double-edged sword in gastric mucosa.