Novel Antithrombotic Diadenosine Tetraphosphate Analogs

新型抗血栓四磷酸二腺苷类似物

• 批准号: 8697167
• 负责人: Ivan B Yanachkov
• 金额: $ 85.9万
• 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/8697167
• 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：许多常见的病理或干预措施都可能导致不必要的血小板激活。动脉血栓形成和随之而来的急性缺血事件，如心肌梗塞和中风，是发达国家死亡、丧失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重大的社会影响。在这个项目的前几个阶段，我们开发了一系列新的双腺苷四磷酸(Ap4A)类似物，它们通过一种独特的新机制抑制血小板聚集，针对血小板ADP受体P2Y1和P2Y12。我们的研究表明，这种同时靶向可能在抑制血小板聚集方面具有协同作用。同时瞄准两个协同靶点还可以提供额外的安全度，以防止不受欢迎的场外靶点副作用。在第二阶段，我们研究了He类药物的特异性和选择性，并确定了一种具有体内疗效的候选药物，用于进一步的开发。该候选药物(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，在已建立的类似不稳定心绞痛的复发性血栓形成的临床前犬模型(“Folts模型”)中，它显示出很高的抗血栓活性。在该模型中，在1.8g/kg/min的输注剂量下，它完全消除了损伤和受限冠状动脉的周期性血流变化(复发血栓形成)。在剂量递增研究中，镉对大鼠的血小板反应性有深远的影响，只有在所研究的最高剂量(比最大有效剂量高出100倍)时，出血时间的增加相对较小。在任何剂量下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，在内皮依赖的豚鼠主动脉松弛模型中具有良好的安全性。此外，CD的抗血小板作用是可逆的，其体内活性具有非常快的起效和抵消作用，并很快从体循环中消失。我们还证明了CD可以在多克尺度上合成和纯化。鉴于这一类别的独特性质和在第二阶段取得的可喜结果，我们建议继续CD的临床前开发，以获得一揽子数据，使我们能够在IND提交后获得投资者或合作伙伴的资金，以启动临床测试，或者将CD授权给MAR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进展，并且由于急性冠状动脉综合征患者的死亡率、复发率和主要出血事件都很高，因此迫切需要新的抗血小板药物：a)可以减少缺血事件，而不会导致大量出血；b)效果的患者间变异性低；c)起效快，确保立即保护患者；d)效果具有快速可逆性，因此在FIAL诊断和干预策略到位之前就可以开始治疗。当今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COX-1和P2Y12血小板受体。对这两种药物的反应有限，通常被称为“耐药”，在相当数量的患者中发生，并与不良的临床结果有关。目前还没有发现既能抑制P2Y1受体又能抑制P2Y12受体的药物。对于需要抗血小板治疗、可能有出血并发症风险或可能需要手术干预的患者，目前还没有快速可逆的(1-2小时内)注射抗血小板药物可供临床使用。因此，我们期待CD的进一步发展将导致一种新的抗血栓药物，具有更好的安全性和有效性，以及满足以下要求的治疗特性 重要的未得到满足的临床需求，并降低急性冠状动脉综合征患者的死亡率。