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）：对新抗血小板药物的开发产生了浓厚的兴趣，这些药物将直接和可逆地起作用，避免了当前选择的氯吡格雷药物的明显问题。多丁丁糖苷P1，P4-四磷酸（AP4A）及其膦酸酯和硫代膦酸酯类似物，例如AP（S）PCHCLPP（S）A抑制血小板在体外抑制血小板聚集，并在体内表现出抗抑制性活性，急性和慢性毒性低。该类已被证明可逆地抑制血小板ADP受体，但确切的受体靶标尚不清楚。现有数据表明P2Y1靶向，但也不排除P2Y12抑制作用。 BIS核苷的多磷酸在血液中迅速降解，但是较稳定的膦酸酯的发展受到不适合大规模制备的无效合成方法的限制。我们发现了一种基于新的试剂类别合成二核糖苷四磷酸盐和四膦酸盐的新型，高产量的方法：焦磷酸盐和甲基二膦酸酯的稳定但反应性的双咪唑层。此外，已经描述了核苷磷酸盐的新型硼酸衍生物，其特性（例如化学和酶促稳定性以及低毒性）的特性相当组合，使其可作为生物试剂和治疗剂有用。但是，尚未描述二核糖苷四磷酸或四膦酸盐的硼烷衍生物。我们建议利用新的合成方法来准备选定的硼烷基-AP4A类似物，并作为对照，硫代膦酸AP（S）PCHCLPP（S）A，以研究其抗血小板活性，并确定其对P2Y1，P2Y1，P2Y12，以及P2Y12和P2X1受体的拮抗剂/激动剂。我们还将测量大鼠，狗和人血浆中新的Borano-AP4A类似物的稳定性。我们的直接目标是验证和进一步开发我们合成双核苷多磷酸盐的新突破方法，以确定AP4A类似物的类别是否靶向P2Y1，甚至更好，P2Y1和P2Y12血小板受体，以及证明具有治疗性的潜在和血浆稳定性的borananyl boranyyl Borag-n-Nucletiide。我们的远距离目标是发现用于治疗动脉血栓形成的新颖化合物和方法，尤其是，靶向血小板P2Y1的快速和可逆性作用抗血小板剂，或者更好的是P2Y1和P2Y12受体，以补充现有的抗血小板治疗剂，主要靶向血小板P2Y12受体。公共卫生相关性声明该项目将导致一种有效的抗血栓形成药物，该药物将用于治疗动脉血栓形成。候选药物将直接和可逆地抑制与血小板聚集有关的一种或两个受体，并且不会具有当前药物（如氯吡格雷）的缓慢和可变作用的缺点。新药将补充正在开发的动脉血栓形成的相关药物。