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

与到达医院后治疗的巨大进步相比，院前治疗的改善相对较少。在ST段抬高型心肌梗死（STEMI）患者的院前治疗中，与标准口服阿司匹林一起使用强效aIIbB 3拮抗剂有可能降低早期死亡率和未来6-12个月内充血性心力衰竭的发生。这一假设基于证据，证据显示症状发作后立即使用其他aIIbB 3拮抗剂（沿着阿司匹林）治疗可中止血栓性心肌缺血向不可逆心脏损伤的进展，并降低死亡率。此外，我们预计安全性良好，因为患者在院前环境中既不需要抗凝也不需要动脉穿刺，并且效果将在2-4小时内消失。目前的aIIbB 3拮抗剂都必须静脉内给药，这是院前治疗的主要缺点。我们目前正在收集所需的研究性新药（IND）数据，以推进RUC-4，一种新型的aIIbB 3拮抗剂，用于人体研究。基于aIIbB 3的晶体学结构研究，RUC-4被设计为对aIIbB 3具有特异性，并且具有独特的作用机制，不仅防止配体结合，而且防止由在R（K）GD序列上模式化的当前aIIbB 3拮抗剂诱导的3亚基中的构象变化，所述构象变化涉及引起血小板减少症和反常受体激活。RUC-4还被设计为具有高溶解度（80 mg/ml），使得可能的人剂量（1 mg/kg）可以通过自动注射器以1 ml给药。基于对小鼠和非人灵长类动物的研究，RUC-4在肌内注射后被迅速吸收。在非人灵长类动物中，以1.93 mg/kg的剂量IM给予0.27 ml后，血小板聚集在15分钟内消除，4.5小时后血小板聚集部分恢复。较低剂量（0.47 ml; 1 mg/kg）在15分钟时产生部分抑制聚集，在30分钟时产生完全抑制，在2小时时部分恢复聚集。因此，RUC 4的当前概况与ST段抬高型心肌梗死（STEMI）患者的院前治疗的预期需求相匹配。

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).