Novel Antithrombotic Diadenosine Tetraphosphate Analogs

描述（由申请人提供）：人们对开发新的抗血小板药物作为直接和可逆作用的抗血栓药物非常感兴趣，避免了目前选择的药物氯吡格雷的记录缺陷。合成的ATP类似物是ADP依赖性血小板P2 Y受体之一的有效拮抗剂，目前正作为抗血栓形成药物进行临床试验。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PAp（S）pCHClp 2（S）A（“Avathrom”）在体外抑制血小板聚集，并在体内显示抗血栓形成活性，但在高剂量下。现有数据表明P2 Y1靶向，但也不排除P2 Y12抑制。我们已经发现了用于合成二核苷四磷酸和四膦酸酯的新的高效方法，这将首次使修饰的Ap 4A衍生物的有效制备成为可能。一种方法是基于一种新的试剂类-稳定的，但反应性的焦磷酸和亚甲基双膦酸酯的双咪唑-和廉价的起始材料，导致在高产率的对称产品。也适用于不对称类似物的另一种方法依赖于核苷-5 '-偏三磷酸或核苷-5'-偏三膦酸酯与核苷单磷酸之间的有效反应。我们建议利用新的合成方法来制备对称和不对称的腺嘌呤修饰的Ap 4A类似物，基于ATP和ADP类似物的现有SAR数据进行修改，目的是创建血小板P2 Y1和/或P2 Y12受体的有效拮抗剂，并且可能是靶向这两种受体的独特的一类抗血小板药物。将测定抗血小板效力和血小板形状改变活性，并测量新化合物对P2 Y1、P2 Y12和P2 X1受体的拮抗剂/激动剂性质。我们还将测量选定的新类似物在大鼠、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用于合成双核苷多磷酸的突破性方法，以确定这类Ap 4A类似物是否靶向P2 Y1，P2 Y12，甚至更好，P2 Y1和P2 Y12血小板受体，并证明新型Ap 4A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。 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种或两种重要受体，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。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。

DESCRIPTION (provided by applicant): There is significant interest in development of new antiplatelet agents as antithrombotic drugs that act directly and reversibly, avoiding documented drawbacks of the current drug of choice, clopidogrel. A synthetic ATP analog, which is a potent antagonist of one of the ADP- dependent platelet P2Y receptors, is in clinical testing as an antithrombotic drug. Diadenosine P1,P4-tetraphosphate (Ap4A) and its phosphonate and thiophosphonate analogs such as P Ap(S)pCHClp2(S)A ("Avathrom") inhibit platelet aggregation in vitro, and show antithrombotic activity in vivo, but at high doses. Existing data suggest P2Y1 targeting, but do not rule out P2Y12 inhibition as well. We have discovered new, highly efficient methods for synthesis of dinucleoside tetraphosphates and tetraphosphonates that will enable the efficient preparation of modified Ap4A derivatives for the first time. One method is based on a new reagent class - stable but reactive bis-imidazolides of pyrophosphate and methylenebisphosphonates - and inexpensive starting materials, resulting in symmetric products in high yield. The other method, suitable also for unsymmetric analogs, relies on an efficient reaction between nucleoside-5'-metatriphosphates or -5'-metatriphosphonates and nucleoside monophosphates. We propose to exploit the new synthetic methods to prepare symmetric and unsymmetric adenine-modified Ap4A analogs, with modifications based on existing SAR data of ATP and ADP analogs, with the aim to create potent antagonists of platelet P2Y1 and/or P2Y12 receptors, and, possibly, a unique class of antiplatelet agents which targets both receptors. The antiplatelet potency and platelet shape change activity will be determined, and antagonist/agonist properties of the new compounds toward P2Y1, P2Y12, and P2X1 receptors will be measured. We will also measure the stability of selected new analogs in rat, dog, and human plasma. Our immediate goals are to validate and further develop breakthrough methods for synthesis of bis-nucleoside polyphosphates, to determine if the class of Ap4A analogs targets P2Y1, P2Y12, or even better, both P2Y1 and P2Y12 platelet receptors, and to demonstrate the therapeutic potential and plasma stability of novel Ap4A 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. 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 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.