Novel Antithrombotic Diadenosine Tetraphosphate Analogs

新型抗血栓四磷酸二腺苷类似物

• 批准号: 7908697
• 负责人: Ivan B Yanachkov
• 金额: $ 77.97万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908697
• 关键词: ADP Receptors; Acute; Adverse effects; Affinity; Animals; Antiplatelet Drugs; Aorta; Arteries; Arteriosclerosis; Aspirin; Binding; Biological Assay; Bladder; Bleeding time procedure; Blood; Blood Platelets; Brain region; Cangrelor; Canis familiaris; Cause of Death; Cavia; Cell Line; Cell model; Chemicals; Chemistry; Clinical; Complement; Contracts; Coronary Thrombosis; Dependence; Development; Dose; Drug Delivery Systems; Drug Kinetics; Ear; Endothelium; Evaluation; Event; Functional disorder; Funding; Generations; Goals; Hemorrhage; Hemostatic function; Human; Hypertension; Infusion procedures; Intravenous infusion procedures; Lead; Licensing; Ligands; Membrane; Metabolism; Methods; Modeling; Modification; Monitor; Morbidity - disease rate; Myocardial Infarction; Nucleotides; Operative Surgical Procedures; Oryctolagus cuniculus; P2X-receptor; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Platelet Activation; Platelet Aggregation Inhibitors; Platelet aggregation; Plavix; Play; Preparation; Process; Property; Rattus; Recombinants; Relaxation; Reproducibility; Research; Role; Safety; Sales; Secure; Series; Specificity; Stroke; Structure; Structure-Activity Relationship; Therapeutic; Thrombosis; Thrombus; Ticlopidine; Time; Tissue Model; Tissues; Work; analog; analytical method; base; clopidogrel; diadenosine tetraphosphate; drug candidate; drug development; follow-up; in vivo; inhibitor/antagonist; inorganic phosphate; novel; pre-clinical; public health relevance; purinoceptor P2Y1; purinoceptor P2Y6; radioligand; receptor; response; scale up; success; therapy development; thienopyridine; trend

DESCRIPTION (provided by applicant): Phase I resulted in our discovery of low nanomolar level inhibitors of ADP-induced human platelet aggregation, with a unique mechanism of action, that warrant further development as first-in-class antithrombotic drugs. We developed a novel, efficient, high yield method to prepare a series of base and phosphate modified derivatives of diadenosine tetraphosphate (Ap4A). The proposed modifications revealed clear structure-activity trends, and led to the synthesis of highly potent inhibitors of human platelet aggregation that are also stable in plasma. We investigated for the first time the mechanism of action of this class at the level of the three platelet purinoreceptors (P2X1,P2Y1 and P2Y12), and showed that Ap4A and its analogs antagonize both P2Y1 and P2Y12. Moreover this unprecedented simultaneous inhibition of both platelet ADP dependent platelet receptors by a single ligand appears to be highly synergistic - IC50'sfor inhibition of ADP-induced platelet aggregation for the most active compounds is one to two order of magnitude lower than the corresponding IC50'sof inhibition of P2Y1 and P2Y12. Thus these compounds represent a new class of antiplatelet, and, ultimately, antithrombotic drugs with a novel mechanism of action. The specific aims are to 1, expand and tune the structure:activity relationship for inhibiting human platelet aggregation by synthesis and study of six additional Ap4A analogs, 2, evaluate the selectivity/specificity of the new class of Ap4A derivatives, by studying and quantifying the ability of 3-6 most active compounds to interact with non-platelet P2 receptors, utilizing tissue and recombinant receptor models, 3, optimize and scale up the chemical process of synthesis and purification of the class; 4, determine the basic pharmacokinetic parameters and identify metabolites of the 3 lead compounds candidates after IV administration in rats, and 5, study the aggregation properties of platelets after IV infusion of these candidates in catheterized rats, and 6, confirm the antithrombotic activity of the selected lead compound in the well-established Folts' canine thrombosis model. A single lead preclinical compound (plus backup) will be designated following these studies. Platelets play critical roles in hemostasis and its pathophysyology. Undesired platelet activation is a result of many common pathologies, e.g. hypertension and arteriosclerosis, and leads to excessive platelet aggregation and the generation of occlusive thrombi (thrombosis). The ischemic events that follow, such as myocardial infarction and stroke, are leading causes of death in the developed world, and antiplatelet drugs have been a major focus of drug development. Aspirin and clopidrogel (Plavix(R), $5.9B sales in 2005) are the most popular of the class today. Because of the vast interpatient variability in response to clopidogrel and newer single-receptor targeted drugs under clinical development, and because of the increased bleeding and morbidity in patients receiving clopidogrel, there is a need for the development of fast, direct acting, and rapidly cleared platelet ADP-receptor antagonists. The overall goal of this research is to identify a novel lead antithrombotic compound for human use, which can be licensed to a major pharmaceutical company for further pre-clinical and clinical development, or alternatively can be developed into a drug candidate by us after securing appropriate partnership or funding. PUBLIC HEALTH RELEVANCE: This project will result in an effective antithrombotic drug that will be used to treat arterial thrombosis in the acute setting. The candidate drug will directly and reversibly inhibit two important receptors involved in platelet aggregation, and will not have the drawbacks of slow and variable action of current drugs such as clopidogrel. The new drug will complement related drugs under development for arterial thrombosis.

描述（由申请人提供）：I期研究发现了ADP诱导的人血小板聚集的低纳摩尔水平抑制剂，具有独特的作用机制，值得进一步开发为一流的抗血栓药物。我们发展了一种新的、高效的、高产率的方法来制备一系列的碱基和磷酸酯修饰的四磷酸二腺苷（Ap 4A）衍生物。所提出的修饰揭示了明确的结构-活性趋势，并导致了在血浆中也稳定的高效人血小板聚集抑制剂的合成。我们首次研究了这类药物在三种血小板嘌呤受体（P2 X1，P2 Y1和P2 Y12）水平上的作用机制，并表明Ap 4A及其类似物可拮抗P2 Y1和P2 Y12。此外，单一配体对两种血小板ADP依赖性血小板受体的这种前所未有的同时抑制似乎是高度协同的-对于大多数活性化合物，抑制ADP诱导的血小板聚集的IC 50比抑制P2 Y1和P2 Y12的相应IC 50低一到两个数量级。因此，这些化合物代表了一类新的抗血小板药物，并最终成为具有新作用机制的抗血栓药物。具体目的是1，通过合成和研究六种另外的Ap 4A类似物来扩展和调整抑制人血小板聚集的结构：活性关系，2，通过研究和量化3-6种最具活性的化合物与非血小板P2受体相互作用的能力，利用组织和重组受体模型来评估新类别的Ap 4A衍生物的选择性/特异性，3，优化和扩大合成和纯化该类化合物的化学方法; 4.测定3种先导化合物候选物在大鼠静脉给药后的基本药代动力学参数并鉴定其代谢产物;在静脉输注这些候选物后，在插入导管的大鼠中研究血小板的聚集特性，和6，在良好建立的Folts犬血栓形成模型中证实所选先导化合物的抗血栓形成活性。在这些研究之后，将指定单一的临床前先导化合物（加上备用化合物）。血小板在止血及其病理生理学中起关键作用。不期望的血小板活化是许多常见病理（例如高血压和动脉硬化）的结果，并且导致过度的血小板聚集和闭塞性血栓（血栓形成）的产生。随之而来的缺血性事件，如心肌梗死和中风，是发达国家的主要死亡原因，抗血小板药物一直是药物开发的主要焦点。阿司匹林和氯吡格雷（2005年销售额为59亿美元）是当今最受欢迎的药物。由于对氯吡格雷和临床开发中的新型单受体靶向药物的反应存在巨大的患者间差异，并且由于接受氯吡格雷的患者出血和发病率增加，因此需要开发快速、直接作用和快速清除的血小板ADP受体拮抗剂。本研究的总体目标是确定一种新型的人用抗血栓化合物，该化合物可以授权给一家大型制药公司进行进一步的临床前和临床开发，或者在获得适当的合作伙伴关系或资金后，由我们开发成候选药物。 公共卫生关系：该项目将产生一种有效的抗血栓药物，用于治疗急性动脉血栓形成。该候选药物将直接可逆地抑制参与血小板聚集的两种重要受体，并且不会具有目前药物如氯吡格雷的缓慢和可变作用的缺点。这种新药将补充正在开发的治疗动脉血栓形成的相关药物。