Novel Antithrombotic Diadenosine Tetraphosphate Analogs

描述：不希望的血小板活化可以是许多常见的病理或干预的结果。在发达国家，动脉血栓形成及其引发的急性缺血事件，如心肌梗死和中风，是导致死亡、丧失行为能力和医疗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，这一领域的进展可以产生显著的社会影响。在本项目前期，我们开发了一系列新的四磷酸二腺苷（Ap4A）类似物，它们通过一种独特的新机制抑制血小板聚集，同时靶向血小板ADP受体P2Y1和P2Y12。我们的研究表明，这种同时靶向可能对血小板聚集抑制有协同作用。同时靶向两个协同靶标也可以提供额外的安全边际，以防止不希望的场外靶标副作用。在II期，我们研究了这类药物的特异性和选择性，并确定了一个在体内有效的候选药物进行进一步的开发。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，它在临床前建立的模拟不稳定心绞痛的犬复发性血栓模型（“Folts模型”）中显示出高抗血栓活性。在该模型中，在1.8¿g/kg/min的注射剂量下，完全消除了损伤和受限冠状动脉循环血流变化（复发血栓形成）。在一项大鼠剂量递增研究中，CD对血小板反应性有深远的影响，只有在研究的最高剂量（比最大有效剂量高100倍）时，出血时间才有相对较小的增加。在任何剂量下，它对血流动力学参数也没有影响。它不作为人P2Y2、P2Y4、P2Y6或P2X1受体的激动剂或拮抗剂，在内皮细胞p2y依赖性豚鼠主动脉舒张模型中具有良好的安全裕度。此外，CD的抗血小板作用是可逆的，具有非常快的起效和体内活性的抵消，并迅速从体循环中清除。我们还证明了CD可以在多克尺度上合成和纯化。鉴于该类药物的独特特性和在II期获得的有希望的结果，我们建议继续CD的临床前开发，以获得一揽子数据，使我们能够确保投资者或合作伙伴在IND提交后启动临床试验，或者将CD授权给一家大型制药公司进行进一步的临床开发。尽管最近新型抗血小板药物的开发取得了进展，并且由于急性冠状动脉综合征患者的高死亡率、复发率和主要出血事件，因此迫切需要新的抗血小板药物，以便：A)可以减少缺血事件而不引起过度出血，b)效果的患者间可变性低，c)作用迅速，确保立即保护患者，d)效果具有快速可逆性，因此可以在最终诊断和干预策略到位之前开始治疗。目前临床应用的主要抗血小板药物

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.