RUC-4: A Novel [alpha]IIb[beta]3 Antagonist for Prehospital Therapy of Myocardial Infarction.
Li, Jihong *; Vootukuri, Spandana *; Shang, Yi; Negri, Ana; Jiang, Jian-kang; Nedelman, Mark; Diacovo, Thomas G.; Filizola, Marta; Thomas, Craig J.; Coller, Barry S.
Arteriosclerosis, Thrombosis & Vascular Biology.
34(10):2321-2329, October 2014.
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Objective-: Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an [alpha]IIb[beta]3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule [alpha]IIb[beta]3 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.
Approach and Results-: RUC-4 was [almost equal to]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 [alpha]IIb[beta]3 versus [alpha]V[beta]3, did not prime the receptor to bind fibrinogen, or induce changes in [beta]3 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.
Conclusions-: 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.
(C) 2014 American Heart Association, Inc.