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Diadenosine Boranotetraphosph(on)ates as Antithrombotic Drugs

二腺苷硼四磷酸盐作为抗血栓药物

基本信息

批准号：
7222361
负责人：
Ivan B Yanachkov
金额：
$ 29.97万
依托单位：
GLSYNTHESIS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-12 至 2008-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7222361
关键词：
ADP Receptors Acute Adverse effects Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Antiplatelet Drugs Antiviral Agents Area Arteriosclerosis Aspirin Asthma Biological Bis(5&apos -Nucleosidyl)Tetraphosphate Blood Blood Platelets Blood Vessels Blood flow Borohydrides Brain Calcium Canis familiaris Cause of Death Charge Chemicals Chronic Class Clinical Clinical Trials Complement Complex Condition Cyclic AMP Cytochrome P450 Data Dependence Development Dinucleoside Polyphosphates Diphosphates Drug Interactions Enzymes Evaluation Event Family Generations Glaucoma Goals HIV Hemorrhage Hemostatic function Hepatitis C virus Human Hypertension In Vitro Individual Lead Light Liver Measurement Measures Metabolism Methods Modeling Myocardial Infarction Nucleosides Oligonucleotides Operative Surgical Procedures Optics Oryctolagus cuniculus P-Selectin Parents Pathology Patients Personal Communication Personal Satisfaction Pharmaceutical Preparations Phase I Clinical Trials Phosphoric Monoester Hydrolases Physical condensation Physiological Plasma Platelet Activation Platelet aggregation Play Polyphosphates Preparation Procedures Process Prodrugs Property Public Health Purpose Range Rate Rattus Reaction Reagent Reducing Agents Research Resistance Risk Role Sales Shapes Staging Stroke Structure Surface Synthesis Chemistry System Testing Therapeutic Therapeutic Uses Thrombosis Thrombus Time Today Toxic effect Toxicology Variant analog base bisphosphonate carbene chemical property clopidogrel cost diadenosine 5&apos ,5&apos &apos &apos -(P(1),P(4)-dithio-P(2),P(3)-chloromethylene)tetraphosphate diadenosine tetraphosphate diborane drug development ecto-nucleotidase extracellular in vivo inhibitor/antagonist inorganic phosphate interest liver function liver metabolism monocyte neutrophil novel nuclease nucleotide analog phosphonate phosphorothioate practical application preclinical study purinoceptor P2Y1 receptor release of sequestered calcium ion into cytoplasm research study response tool

项目摘要

DESCRIPTION (provided by applicant): There is significant interest in development of new antiplatelet drugs that will act directly and reversibly, avoiding clear problems with the current drug of choice, clopidogrel. Diadenosine P1,P4-tetraphosphate (Ap4A) and its phosphonate and thiophosphonate analogs such as Ap(S)pCHClpp(S)A inhibit platelet aggregation in vitro, and show antithrombotic activity in vivo, with low acute and chronic toxicity. The class has been shown to reversibly inhibit platelet ADP receptors, but the exact receptor target is not known. Existing data suggest P2Y1 targeting, but does not rule out P2Y12 inhibition as well. Bis-nucleoside polyphosphates are rapidly degraded in blood, but development of the more stable phosphonates is limited by inefficient synthesis methods that are unsuitable for large scale preparation. We have discovered a new, high yield method for synthesis of dinucleoside tetraphosphates and tetraphosphonates based on a new reagent class: stable but reactive bis-imidazolides of pyrophosphate and methylenebisphosphonates. In addition, novel boranyl derivatives of nucleoside phosphates have been described with a remarkable combination of properties, such as chemical and enzymatic stability and low toxicity, that make them useful as biological reagents and therapeutics. No boranyl derivatives of dinucleoside tetraphosphates or tetraphosphonates, however, have been described. We propose to exploit the new synthetic method to prepare selected boranyl-Ap4A analogs and, as control, the thiophosphonate Ap(S)pCHClpp(S)A, in order to study their antiplatelet activity, and to determine their antagonist/agonist properties toward P2Y1, P2Y12, and P2X1 receptors. We will also measure the stability of the new borano-Ap4A analogs in rat, dog, and human plasma. Our immediate goals are to validate and further develop our new breakthrough method for synthesis of bis-nucleoside polyphosphates, to determine if the class of Ap4A analogs targets P2Y1, or even better, both P2Y1 and P2Y12 platelet receptors, and to demonstrate the therapeutic potential and plasma stability of novel boranyl bis-nucleotide analogs. Our long range goals are to discover novel compounds and methods for treatment of arterial thrombosis, and more particularly, a fast and reversibly acting antiplatelet agent targeting platelet P2Y1, or better, both P2Y1 and P2Y12 receptors, to complement existing antiplatelet therapeutics which mainly target the platelet P2Y12 receptor. Public Health Relevance Statement This project will result in an effective antithrombotic drug that will be used to treat arterial thrombosis. The candidate drug will directly and reversibly inhibit one or both of the 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）：人们对开发新的抗血小板药物非常感兴趣，这些药物将直接和可逆地起作用，避免当前选择的药物氯吡格雷的明显问题。二腺苷P1，P4-四磷酸（Ap 4A）及其膦酸酯和硫代膦酸酯类似物如Ap（S）pCHClpp（S）A在体外抑制血小板聚集，在体内显示抗血栓形成活性，具有低的急性和慢性毒性。该类已被证明可逆地抑制血小板ADP受体，但确切的受体靶点尚不清楚。现有数据表明P2 Y1靶向，但也不排除P2 Y12抑制。双核苷多磷酸在血液中迅速降解，但更稳定的膦酸酯的开发受到不适合大规模制备的低效合成方法的限制。我们发现了一种新的，高产率的方法，用于合成二核苷四磷酸和四膦酸酯的基础上的一个新的试剂类：稳定的，但反应性的焦磷酸和亚甲基双膦酸酯的双咪唑。此外，已经描述了核苷磷酸的新型硼烷基衍生物，其具有显著的性质组合，例如化学和酶稳定性以及低毒性，这使得它们可用作生物试剂和治疗剂。然而，尚未描述二核苷四磷酸或四膦酸酯的硼烷基衍生物。我们建议利用新的合成方法来制备选定的硼烷基-Ap 4A类似物，并以硫代膦酸酯Ap（S）pCHClpp（S）A作为对照，以研究它们的抗血小板活性，并确定它们对P2 Y1、P2 Y12和P2 X1受体的拮抗剂/激动剂性质。我们还将测量新borano-Ap 4A类似物在大鼠、犬和人血浆中的稳定性。我们的近期目标是验证和进一步开发我们用于合成双核苷多磷酸的新的突破性方法，以确定Ap 4A类似物类是否靶向P2 Y1，或者更好地靶向P2 Y1和P2 Y12血小板受体，并证明新型硼烷基双核苷酸类似物的治疗潜力和血浆稳定性。我们的长期目标是发现用于治疗动脉血栓形成的新化合物和方法，更具体地，发现靶向血小板P2 Y1或更好地靶向P2 Y1和P2 Y12受体两者的快速且可逆作用的抗血小板剂，以补充主要靶向血小板P2 Y12受体的现有抗血小板治疗剂。公共卫生相关性声明本项目将产生一种有效的抗血栓药物，用于治疗动脉血栓形成。候选药物将直接和可逆地抑制参与血小板聚集的一种或两种受体，并且将不具有当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。