Novel Antithrombotic Diadenosine Tetraphosphate Analogs

新型抗血栓四磷酸二腺苷类似物

• 批准号: 7272517
• 负责人: Ivan B Yanachkov
• 金额: $ 33.32万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7272517
• 关键词: ADP Receptors; Address; Adenine; Adenosine; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antiplatelet Drugs; Antiviral Agents; Arteriosclerosis; Aspirin; Asthma; Bis(5' -Nucleosidyl)Tetraphosphate; Blood Platelet Antagonists; Blood Platelets; Calcium; Cangrelor; Canis familiaris; Cardiovascular system; Cause of Death; Cessation of life; Chemicals; Chemistry; Class; Clinical; Complement; Coronary; Coronary Thrombosis; Cyclic AMP; Data; Dependence; Development; Diphosphates; Dose; Drug Delivery Systems; Event; Family; Generations; Glaucoma; Goals; HIV; Hemorrhage; Hemostatic function; Hepatitis C virus; Human; Hypertension; In Vitro; Lead; Light; Measurement; Measures; Metabolism; Methods; Modeling; Modification; Morbidity - disease rate; Myocardial Infarction; New Agents; Nucleosides; Operative Surgical Procedures; Optics; Oryctolagus cuniculus; P-Selectin; Parents; Pathology; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Platelet Activation; Platelet aggregation; Play; Polyphosphates; Preparation; Procedures; Property; Range; Rate; Rattus; Reaction; Reagent; Research; Role; Sales; Shapes; Stroke; Structure; Structure-Activity Relationship; Surface; Syndrome; Techniques; Testing; Therapeutic; Thrombosis; Thrombus; Ticlopidine; Time; Today; Toxic effect; Toxicology; Work; adenosine 3' -phosphate-5' -phosphate; analog; base; bisphosphonate; carbene; clopidogrel; design; diadenosine 5' ,5' ' ' -(P(1),P(4)-dithio-P(2),P(3)-chloromethylene)tetraphosphate; diadenosine tetraphosphate; drug development; in vivo; inhibitor/antagonist; interest; monocyte; neutrophil; novel; nucleoside monophosphate; phosphonate; practical application; preclinical study; purinoceptor P2Y1; rapid technique; receptor; release of sequestered calcium ion into cytoplasm; research clinical testing; response; scaffold; therapy development; thienopyridine; tool

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.

描述（由申请人提供）：人们对开发新型抗血小板药物作为直接且可逆地发挥作用的抗血栓药物非常感兴趣，从而避免了当前选择的药物氯吡格雷的已记录的缺点。一种合成的 ATP 类似物是 ADP 依赖性血小板 P2Y 受体之一的有效拮抗剂，目前正在作为抗血栓药物进行临床测试。二腺苷 P1,P4-四磷酸 (Ap4A) 及其磷酸盐和硫代磷酸盐类似物，例如 P Ap(S)pCHClp2(S)A (“Avathrom”) 在体外抑制血小板聚集，并在体内显示出抗血栓形成活性，但在高剂量时。现有数据表明 P2Y1 靶向，但也不排除 P2Y12 抑制。我们发现了新的、高效的二核苷四磷酸和四磷酸合成方法，这将首次能够有效制备修饰的 Ap4A 衍生物。一种方法基于一种新的试剂类型——焦磷酸盐和亚甲基二膦酸盐的稳定但具有反应性的双咪唑化物——和廉价的起始材料，从而以高产率产生对称产物。另一种方法也适用于不对称类似物，它依赖于核苷-5'-偏三磷酸酯或-5'-偏三磷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腺嘌呤修饰的 Ap4A 类似物，并根据 ATP 和 ADP 类似物的现有 SAR 数据进行修改，目的是创建血小板 P2Y1 和/或 P2Y12 受体的有效拮抗剂，并可能创建一类针对这两种受体的独特抗血小板药物。将确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 P2Y1、P2Y12 和 P2X1 受体的拮抗剂/激动剂特性。我们还将测量选定的新类似物在大鼠、狗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合成双核苷多磷酸的突破性方法，以确定 Ap4A 类似物类是否靶向 P2Y1、P2Y12，甚至更好地靶向 P2Y1 和 P2Y12 血小板受体，并证明新型 Ap4A 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方法，更具体地说，是一种针对血小板 P2Y1 或更好的是 P2Y1 和 P2Y12 受体的快速且可逆作用的抗血小板药物，以补充主要针对血小板 P2Y12 受体的现有抗血小板疗法。 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。该候选药物将直接、可逆地抑制一种或两种参与血小板聚集的重要受体，并且不会存在现有药物如氯吡格雷作用缓慢且多变的缺点。该新药将补充正在开发的治疗动脉血栓形成的相关药物。

项目成果

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.

• DOI: 10.1016/j.ejmech.2015.10.055
• 发表时间: 2016-01-01
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Yanachkov IB;Chang H;Yanachkova MI;Dix EJ;Berny-Lang MA;Gremmel T;Michelson AD;Wright GE;Frelinger AL 3rd
• 通讯作者: Frelinger AL 3rd