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  • RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction.

RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction.

Arteriosclerosis, thrombosis, and vascular biology (2014-08-26)
Jihong Li, Spandana Vootukuri, Yi Shang, Ana Negri, Jian-Kang Jiang, Mark Nedelman, Thomas G Diacovo, Marta Filizola, Craig J Thomas, Barry S Coller
ABSTRACT

Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. RUC-4 was ≈ 20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60-80 mg/mL). It shared RUC-2's specificity for αIIbβ3 versus αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours. RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

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Iron(III) chloride, sublimed grade, ≥99.9% trace metals basis
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Iron(III) chloride, anhydrous, powder, ≥99.99% trace metals basis
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Iron(III) chloride solution, purum, 45% FeCl3 basis
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Iron(III) chloride solution, 0.2 M in 2-methyltetrahydrofuran
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TDA Reagent, suitable for microbiology
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