Inhibitory Mechanisms of Lusianthridin on Human Platelet Aggregation

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC₅₀ of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC₅₀ value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.     

川芎嗪-丁苯酞衍生物的设计、合成及抗血小板聚集活性研究

以邻苯二甲酸酐和川芎嗪为原料,经自由基取代、正丁基锂亲核加成、对甲基苯磺酸催化脱水、Pd/C加氢还原、水解、酯化等反应合成了3个川芎嗪与丁苯酞拼合衍生物,其结构经1HNMR、13CNMR和HR-MS确证.其中(3,5,6-三甲基吡嗪-2-基)甲基-2-戊酰基苯甲酸酯对由腺苷二磷酸(ADP)诱导的血小板聚集活性抑制率IC50为0.26 mmol/L,优于母体化合物川芎嗪和丁苯酞,是具有良好开发前景的候选化合物.     

氯吡格雷生产技术研究进展

氯吡格雷早期的生产方法主要为外消旋对映体的拆分法,近年来发展了多种利用手性砌块进行不对称合成的技术。对氯吡格雷生产技术进行了介绍,并比较了各种生产技术的优缺点。     

Role of platelets in blood-biomaterial interactions

Over 2 million cardiovascular procedures are performed annually in the United States. Every one of these procedures requires some period of contact with blood with several different biomaterials used in the manufacture of assist devices or implant devices. In view of the increasing importance of the biomaterials in clinical practice, it would be timely to review briefly physicochemical characterization as well as biological evaluations. Blood compatibility encompasses a variety of events associated with blood interaction with the biomaterials used in various procedures. Two separate coagulation mechanisms are involved (arterial and venous) depending upon the flow characteristics. At least three interacting factors modulate normal hemostasis and the pathogenesis of thromboembolic events. They are the state of activation of coagulation cascade, circulating levels of thrombin and fibrinogen and relative activity of platelets. In this overview we discuss the current concepts on the role of platelets in blood-biomaterial interactions. When blood contacts a biomaterial surface a variety of blood components interact with the surface. Some of the key players in platelet activation on biomaterial surface include fibrinogen and von Willebrand factor. Currently available antiplatelet drugs effectively block aggregation and secretion induced by physiological agonists such as epinephrine, adenosine diphosphate and thromboxane in suspension. However, they do not prevent platelet interaction on biomaterial surfaces. Mechanisms involved in platelet activation in suspension and on surfaces as well as the pharmacology of newer antiplatelet drugs will be discussed.     

Current and Novel Antiplatelet Therapies for the Treatment of Cardiovascular Diseases

Over the last decades, antiplatelet agents, mainly aspirin and P2Y₁₂ receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.     

4‐Benzothiazole‐7‐hydroxyindolinyl Diaryl Ureas Are Potent P2Y1 Antagonists with Favorable Pharmacokinetics: Low Clearance and Small Volume of Distribution

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y₁ antagonists may have lower bleeding liabilities than P2Y₁₂ antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7‐hydroxyindolinyl diaryl ureas. When dosed orally, 4‐trifluoromethyl‐7‐hydroxy‐3,3‐dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF₃ group in 4 was then transformed to various groups via a novel one‐step synthesis, yielding a series of potent P2Y₁ antagonists. Among them, the 4‐benzothiazole‐substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.     

Expedient synthesis of 2-alkylthio-N6-aryladenosines from guanosine

A general approach for the synthesis of 2-alkylthio-N⁶-aryladenosine was developed from the commercially available guanosine through the acetyl protection, chlorination, diazotization-alkylthionation, aromatic nucleophilic substitution and deacetylation. Two approaches were designed for the transformation of 2-amino-6-chloroguanosine to 2-alkylthio-N⁶-aryladenosines but only the one with diazotization-alkylthionation first could afford the target molecules. Both electron-rich and deficient anilines can afford the desired products in moderate to good yield. Finally, under the optimized condition, 20 2-alkylthio-N⁶-aryladenosines were synthesized, 5 of which exhibit poor antiplatelet aggregation activities.     

新型抗血小板药氯吡格雷研究进展

抗血小板治疗可以有效预防和治疗血栓性疾病，氯吡格雷是一种新型安全高效的抗血小板药物。简要综述了氯吡格雷的药理学特性、与其他抗血小板药物的比较，以及国内外对其各种合成方法的研究进展。     

Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation

Peripheral artery disease (PAD) is a major cause of morbidity and mortality but it is usually underdiagnosed and undertreated. Patients with PAD present dysregulated procoagulant, anticoagulant, and fibrinolytic pathways leading to arterial and venous thrombosis. The risk of several ischemic-related complications could be mitigated with appropriate antithrombotic therapy, which plays a central role in all types of PAD. For years, antiplatelets have been indicated in patients with symptomatic PAD or those who have undergone revascularization. Unfortunately, a non-negligible proportion of patients with PAD will suffer from adverse events during the follow-up, even despite proper medical therapies for the prevention of PAD complications. Thus, there is room for improving clinical outcomes in these patients. Given the implication of both, primary and secondary hemostasis in arterial thrombosis and the pathophysiology of PAD, the combination of antiplatelets and anticoagulants has emerged as a potential antithrombotic alternative to antiplatelets alone. In this narrative review article, we have highlighted the most recent evidence about antithrombotic therapy in PAD patients, with a special focus on oral anticoagulation. Certainly, COMPASS and VOYAGER PAD trials have shown promising results. Thus, rivaroxaban in combination with aspirin seem to reduce cardiovascular outcomes with a similar bleeding risk compared to aspirin alone. Nevertheless, results from real-world studies are needed to confirm these observations, and other trials will provide novel evidence about the safety and efficacy of emerging anticoagulant agents.