Development of a novel aIIbB3 receptor antagonist for pre-hospital myocardial infarction therapy

开发用于院前心肌梗死治疗的新型 aIIbB3 受体拮抗剂

• 批准号: 10263799
• 负责人: Craig Thomas
• 金额: $ 25.2万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263799
• 关键词: Aspirin; Cessation of life; Clinical; Collaborations; Congestive Heart Failure; Data; Development; Disadvantaged; Dose; Hospitals; Hour; Human; Individual; Intramuscular Injections; Intravenous; Investigational Drugs; Ligand Binding; Molecular Conformation; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Oral; Patients; Pattern; Physicians; Platelet aggregation; Pre-hospital setting; Quality of life; Reagent; Receptor Activation; Safety; Solubility; Structure; Symptoms; Therapeutic Intervention; Thrombocytopenia; Tissues; base; design; experience; heart damage; mortality; nonhuman primate; novel; prevent; receptor

There has been relatively little improvement in pre-hospital therapy compared to the dramatic advances in therapy after arriving to the hospital. The addition of a potent aIIbB3 antagonist administered alongside standard oral aspirin in the pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI) has the potential to decrease early mortality and the development of congestive heart failure during the next 6-12 months. This hypothesis is based on evidence showing that therapy with other aIIbB3 antagonists (along with aspirin) soon after symptom onset can abort the progression of thrombotic myocardial ischemia to irreversible cardiac damage and decrease mortality. Moreover, we expect a favorable safety profile since patients will neither be anticoagulated nor undergo arterial access in the pre-hospital setting, and the effects will wear off within 2-4 hours. The current aIIbB3 antagonists all must be administered intravenously, a major disadvantage for pre-hospital therapy. We currently are gathering the needed Investigational New Drug (IND)-enabling data to advance RUC-4, a novel aIIbB3 antagonist, to human studies. Based on crystallographic structural studies of aIIbB3, RUC-4 was designed to be specific for aIIbB3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the 3 subunit induced by current aIIbB3 antagonists patterned on the R(K)GD sequence that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4 was also designed to have high solubility (80 mg/ml) so that the likely human dose (1 mg/kg) can be administered in 1 ml by autoinjector. Based on studies in mice and non-human primates, RUC-4 is rapidly absorbed after intramuscular injection. In non-human primates, platelet aggregation was eliminated within 15 minutes after a 0.27 ml IM dose of 1.93 mg/kg with partial return of platelet aggregation after 4.5 hours. A lower dose (0.47 ml; 1 mg/kg) produced partial inhibition of aggregation at 15 minutes, complete inhibition at 30 minutes, and partial return of aggregation at 2 hours. Thus, the current profile for RUC4 matches the anticipated needs for a pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI).

与到达医院后的急剧进步相比，院前治疗的改善相对较少。在接下来的6-12个月内，与标准口服阿司匹林一起添加了有效的AIIBB3拮抗剂，该拮抗剂与标准口服阿司匹林同时在院前治疗的院前治疗中，在院前治疗的院前治疗中，有可能在接下来的6-12个月中降低早期死亡率和充满充血性心力衰竭的发展。该假设是基于证据表明症状发作后不久对其他AIIBB3拮抗剂（以及阿司匹林）的治疗可以中止血栓性心肌缺血对不可逆的心脏损伤的进展并降低死亡率。此外，我们预计安全性良好，因为在院前环境中既不会抗凝也不会接受动脉通道，并且这种影响会在2-4小时内消失。当前的AIIBB3拮抗剂必须静脉内给药，这是院前治疗的主要缺点。我们目前正在将所需的研究新药（IND）收集到人类研究中，以推动新型AIIBB3拮抗剂RUC-4。 Based on crystallographic structural studies of aIIbB3, RUC-4 was designed to be specific for aIIbB3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the 3 subunit induced by current aIIbB3 antagonists patterned on the R(K)GD sequence that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4也被设计为具有高溶解度（80 mg/ml），因此可以通过自动注射器以1 ml的1 mL施用可能的人剂量（1 mg/kg）。基于对小鼠和非人类灵长类动物的研究，肌内注射后RUC-4被迅速吸收。在非人类灵长类动物中，在0.27 mL IM剂量为1.93 mg/kg之后，在4.5小时后血小板聚集的部分返回后，在15分钟内消除了血小板聚集。较低的剂量（0.47 mL; 1 mg/kg）在15分钟时会部分抑制聚集，在30分钟后完成抑制，并在2小时时部分聚集。因此，RUC4的当前特征与ST节段高度高度心肌梗塞（STEMI）患者的院前治疗的预期需求相匹配。