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：不良血小板活化可能是许多常见病理或干预措施的结果。动脉血栓形成和随之而来的急性缺血事件，例如心肌梗塞和中风，是发达国家死亡、失能和医疗费用上涨的主要原因。因此，抗血小板药物具有巨大的市场份额和临床重要性，该领域的进展可以产生重大的社会影响。 在该项目的前几个阶段，我们开发了一系列新型双四磷酸腺苷 (Ap4A) 类似物，它们通过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具有协同作用。同时瞄准两个协同目标还可以提供额外的安全边际，以防止不希望的异地目标副作用。 在第二阶段，我们研究了该类别的特异性和选择性，并确定了具有体内功效的候选药物以供进一步开发。该候选药物 (CD) 可在低纳摩尔范围内抑制 ADP 和胶原诱导的血小板聚集。此外，它在模拟不稳定心绞痛的复发性血栓形成的完善的临床前犬模型（“Folts 模型”）中显示出高抗血栓活性。在该模型中，以 1.8 µg/kg/min 的输注剂量完全消除了受损和受限冠状动脉中的循环血流变化（复发性血栓形成）。在大鼠的剂量递增研究中，CD 对血小板反应性具有深远的影响，并且仅在所研究的最高剂量（比最大有效剂量高 100 倍）时，出血时间的增加相对较小。它还显示任何剂量对血流动力学参数都没有影响。它不作为人 P2Y2、P2Y4、P2Y6 或 P2X1 受体的激动剂或拮抗剂，并且在内皮 P2Y 依赖性豚鼠主动脉松弛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，其体内活性起效和抵消非常快，并且很快从体循环中清除。我们还证明了CD可以以数克规模合成和纯化。 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. 尽管新型抗血栓药物的开发最近取得了进展，并且由于急性冠脉综合征患者的高死亡率、复发率和严重出血事件，仍然非常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）患者间的效果变异性较低，c）起效快，确保立即保护患者，d）具有快速可逆性 效果，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。大量患者对这两种药物的反应有限，通常称为“耐药性”，并且与不良的临床结果相关。尚未发现能够同时抑制 P2Y1 和 P2Y12 受体的药物。目前尚无快速可逆（1-2小时内）的可注射抗血小板药物可供临床用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。因此，我们期望 CD 的进一步开发能够产生一种安全性和有效性优异、治疗特性满足需求的新型抗血栓药物。 重要的未满足的临床需求，并降低急性冠状动脉综合征患者的死亡率。