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）患者院前治疗中，在标准口服阿司匹林的同时添加一种强效aIIbB3拮抗剂，有可能在未来6-12个月内降低早期死亡率和充血性心力衰竭的发生。这一假设是基于有证据表明，在症状出现后不久使用其他aIIbB3拮抗剂（与阿司匹林一起）治疗可以阻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，我们期望具有良好的安全性，因为患者在院前既不需要抗凝，也不需要动脉通路，而且效果会在2-4小时内消失。目前的aibb3拮抗剂都必须静脉给药，这是院前治疗的一个主要缺点。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aibb3拮抗剂）的人体研究。基于对aIIbB3晶体结构的研究，RUC-4被设计为特异性针对aIIbB3，具有独特的作用机制，不仅可以阻止配体结合，还可以阻止当前aIIbB3拮抗剂诱导的3亚基构象变化，这些构象变化与引起血小板减少和矛盾受体激活有关。RUC-4还具有高溶解度（80 mg/ml），因此可以通过自动注射器在1ml中给药。根据对小鼠和非人灵长类动物的研究，肌肉注射后RUC-4被迅速吸收。在非人类灵长类动物中，0.27 ml 1.93 mg/kg剂量的IM在15分钟内消除血小板聚集，4.5小时后部分恢复血小板聚集。较低剂量（0.47 ml, 1 mg/kg）在15分钟时产生部分聚集抑制，30分钟时完全抑制，2小时时部分恢复聚集。因此，目前RUC4的情况符合ST段抬高型心肌梗死（STEMI）患者院前治疗的预期需求。

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).