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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)：人们对开发直接和可逆的抗血小板新药非常感兴趣，避免了当前选择的药物氯吡格雷的明显问题。二腺苷P1、P4-四磷酸及其类似物如AP(S)pCHClpp(S)A体外抑制血小板聚集，体内显示抗血栓活性，急性和慢性毒性低。该类药物已被证明可以可逆地抑制血小板ADP受体，但确切的受体靶点尚不清楚。现有数据表明，P2Y1靶向，但不排除也抑制了P2Y12。双核糖苷聚磷酸盐在血液中迅速降解，但合成效率低且不适合大规模制备的方法限制了更稳定的磷酸盐的开发。我们发现了一种新的、高产率的合成二核苷四磷酸盐和四膦酸盐的方法，该方法基于一类新的试剂：稳定但活性强的焦磷酸盐和亚甲基双膦酸双咪唑类化合物。此外，核苷磷酸盐的新型硼基衍生物已被描述为具有显著的组合性质，如化学和酶稳定性以及低毒性，使其可用作生物试剂和治疗药物。然而，没有描述二核苷四磷酸盐或四膦酸盐的硼基衍生物。我们建议开发一种新的合成方法来制备选择性的硼酰-Ap4A类似物和作为对照的硫代磷酸盐AP(S)pCHClpp(S)A，以研究它们的抗血小板活性，并确定它们对P2Y1，P2Y12和P2X1受体的拮抗剂和激动剂的性质。我们还将测量新的Borano-Ap4A类似物在大鼠、狗和人血浆中的稳定性。我们目前的目标是验证和进一步开发我们合成双核苷多磷酸的新的突破性方法，确定这类Ap4A类似物是否针对P2Y1，甚至更好地针对P2Y1和P2Y12血小板受体，并证明新型硼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治疗动脉血栓形成的新化合物和新方法，更具体地说，是一种针对血小板P2Y1或更好的P2Y1和P2Y12受体的快速和可逆作用的抗血小板药物，以补充现有的主要针对血小板P2Y12受体的抗血小板药物。公共卫生相关声明该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个或两个受体，并且不会有氯吡格雷等现有药物作用缓慢和可变的缺点。该新药将补充正在开发的治疗动脉血栓形成的相关药物。