Novel Antithrombotic Diadenosine Tetraphosphate Analogs

新型抗血栓四磷酸二腺苷类似物

• 批准号: 8588198
• 负责人: Ivan B Yanachkov
• 金额: $ 112.07万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588198
• 关键词: ADP Receptors; Acute; Adenosine; Adverse effects; Agonist; Antiplatelet Drugs; Aorta; Area; Aspirin; Back; Biological Assay; Bleeding time procedure; Blood Circulation; Blood Platelets; Blood specimen; Bolus Infusion; Canis familiaris; Cardiovascular system; Cause of Death; Cavia; Clinical; Clinical Data; Collagen; Coronary artery; Cyclic GMP; Data; Development; Diagnosis; Dose; Drug Formulations; Drug Kinetics; Endothelium; Event; Funding; Goals; Health Care Costs; Hemorrhage; Hemostatic function; Hour; Human; In Vitro; Infusion procedures; Injectable; Intervention; Intravenous; Licensing; Marketing; Measures; Modeling; Myocardial Infarction; Operative Surgical Procedures; Oral; Outcome; P2X-receptor; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Platelet Activation; Platelet Aggregation Inhibition; Platelet aggregation; Plavix; Play; Process; Property; Qualifying; Rattus; Recurrence; Reference Standards; Regimen; Relative (related person); Relaxation; Resistance; Rest; Risk; Role; Safety; Secure; Series; Site; Social Impacts; Specificity; Stroke; Structure; Testing; Therapeutic; Therapeutic Index; Thrombosis; Time; Toxicokinetics; Toxicology; Treatment Efficacy; Unstable angina; Variant; acute coronary syndrome; analog; analytical method; animal tissue; clopidogrel; cyclooxygenase 1; diadenosine tetraphosphate; genotoxicity; hemodynamics; in vivo; injured; method development; mortality; novel; phase 2 study; pre-clinical; public health relevance; receptor; research clinical testing; response; scale up

DESCRIPTION: Undesired platelet activation can be result of many common pathologies or interventions. Arterial thrombosis and the acute ischemic events that follow, such as myocardial infarction and stroke, are among the leading causes of death, incapacitation, and rising health care costs in the developed world. Therefore antiplatelet drugs have significant market share and clinical importance, and advances in this area can have a significant social impact. In the previous phases of this project we developed a series of new bis-adenosine tetraphosphate (Ap4A) analogs, which inhibit platelet aggregation by a unique new mechanism, targeting both platelet ADP receptors, P2Y1 and P2Y12. Our studies have indicated that this simultaneous targeting might have a synergistic effect on platelet aggregation inhibition. Simultaneous targeting of two synergistic targets can also provide for an additional margin of safety against undesired off-site target side effects. In phase II we studied the specificity and selectivity of he class, and identified a candidate with efficacy in vivo for further development. This candidate (CD) inhibits ADP and collagen induced platelet aggregation in the low nanomolar range. Furthermore, it showed high antithrombotic activity in the well-established preclinical, canine model of recurrent thrombosis mimicking unstable angina ("Folts model"). In this model it completely abolished the cyclic flow variation (recurrent thrombosis) in injured and restricted coronary artery at an infusion dose of 1.8 ¿g/kg/min. In a dose escalation study in rats the CD had a profound effect on platelet reactivity, and relatively small increase of the bleeding time only at the highest dose studied (100 times higher than the maximum efficacious dose). It also showed no effect on hemodynamic parameters at any dose. It did not act as agonist or antagonist of human P2Y2, P2Y4, P2Y6, or P2X1 receptors, and had good safety margin in the endothelium P2Y-dependent guinea pig aorta relaxation model. Moreover, the antiplatelet effect of the CD is reversible, has very fast onset and offset of its in vivo activity, and is quickly clered from the systemic circulation. We also demonstrated that the CD can be synthesized and purified in multi-gram scales. In view of the unique properties of the class and the promising results obtained in phase II, we propose to continue the preclinical development of the CD, in order to obtain the package of data which would enable us to secure investor or partner funding for initiation of clinical testing after IND submission, or alternatively to license the CD to a maor pharmaceutical company for further clinical development. Despite the recent advances in development of new types of antithrombotics and because of the high mortality and recurrence rate and major bleeding events among acute coronary syndrome patients, there is a significant need for new antiplatelet agents that: a) can reduce ischemic events without causing excessive bleeding, b) have low interpatient variability of the effect, c) are fast acting, assuring immediat patient protection, d) have quick reversibility of the effect, so the treatment can start before fial diagnosis and intervention strategy are in place. The main antiplatelet drugs in clinical use today - aspirin and clopidogrel - target platelet COX-1 and P2Y12 platelet receptors, respectively. Limited response to both drugs, often referred to as "resistance", occurs in significant numbers of patients and is associated with poor clinical outcomes. No drugs have yet been identified that inhibit both P2Y1 and P2Y12 receptors. No rapidly reversible (within 1-2 hours) injectable antiplatelet drugs are currently available for clinical use for patients who are in need of antiplatelet therapy, and may be at risk for bleeding complications, or may need surgical intervention. Therefore, we expect the further development of the CD to result in a new antithrombotic drug with superior safety and efficacy, and therapeutic properties that will satisfy important unmet clinical needs, and reduce the mortality rate among patients with acute coronary syndrome.

描述：不期望的血小板活化可能是许多常见病理或干预的结果。动脉血栓形成和随后的急性缺血性事件，如心肌梗死和中风，是发达国家死亡、失能和医疗保健费用上升的主要原因之一。因此，抗血小板药物具有显著的市场份额和临床重要性，并且该领域的进展可以产生显著的社会影响。 在该项目的前几个阶段，我们开发了一系列新的双腺苷四磷酸（Ap 4A）类似物，通过独特的新机制抑制血小板聚集，靶向血小板ADP受体P2 Y1和P2 Y12。我们的研究表明，这种同时靶向可能对血小板聚集抑制具有协同作用。同时靶向两个协同靶标还可以提供针对不期望的非现场靶标副作用的额外安全裕度。 在第二阶段，我们研究了该类的特异性和选择性，并确定了一种在体内具有疗效的候选药物，以供进一步开发。该候选物（CD）在低纳摩尔范围内抑制ADP和胶原诱导的血小板聚集。此外，其在充分建立的临床前、模仿不稳定型心绞痛的复发性血栓形成的犬模型（“Folts模型”）中显示出高抗血栓形成活性。在该模型中，以1.8 μ g/kg/min的输注剂量完全消除了损伤和受限冠状动脉中的循环流量变化（复发性血栓形成）。在大鼠剂量递增研究中，CD对血小板反应性有显著影响，仅在研究的最高剂量（比最大有效剂量高100倍）下出血时间增加相对较小。在任何剂量下，它也对血流动力学参数没有影响。它不作为人P2 Y2、P2 Y 4、P2 Y 6或P2 X1受体的激动剂或拮抗剂，并且在内皮P2 Y依赖性豚鼠主动脉舒张模型中具有良好的安全范围。此外，CD的抗血小板作用是可逆的，具有非常快的体内活性的开始和抵消，并迅速从体循环中清除。我们还证明，CD可以在多克规模的合成和纯化。 鉴于该类药物的独特性质和在II期获得的有希望的结果，我们建议继续进行CD的临床前开发，以获得数据包，使我们能够在IND提交后获得投资者或合作伙伴的资金用于启动临床试验，或者将CD许可给大型制药公司进行进一步的临床开发。 尽管新型抗血栓药物的开发取得了最新进展，但由于急性冠状动脉综合征患者的死亡率、复发率和大出血事件较高，因此仍迫切需要新的抗血小板药物：a）可以减少缺血事件而不引起过度出血，B）具有低的患者间效应变异性，c）是快速作用的，确保立即保护患者，d）具有快速可逆的效果，因此治疗可以在最终诊断和干预策略到位之前开始。目前临床使用的主要抗血小板药物 - 阿司匹林和氯吡格雷分别靶向血小板考克斯-1和P2 Y12受体。对这两种药物的反应有限，通常被称为“耐药”，发生在大量患者中，并与不良的临床结局相关。目前还没有发现同时抑制P2 Y1和P2 Y12受体的药物。对于需要抗血小板治疗、可能存在出血并发症风险或可能需要手术干预的患者，目前尚无快速可逆（1-2小时内）的可注射抗血小板药物可用于临床。因此，我们期望CD的进一步开发能够产生一种新的抗血栓药物，其具有上级安全性和有效性，并且治疗特性将满足 重要的未满足的临床需求，并降低急性冠脉综合征患者的死亡率。