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Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2321-9. doi: 10.1161/ATVBAHA.114.303724. Epub 2014 Aug 21.

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

Author information

1
From the Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY (J.L., S.V., B.S.C.); Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY (Y.S., A.N., M.F.); NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (J.-k.J., C.J.T.); Ekam Imaging, Boston, MA (M.N.); and Departments of Pediatrics and Pathology, Columbia University Medical Center, New York, NY (T.G.D.).
2
From the Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY (J.L., S.V., B.S.C.); Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY (Y.S., A.N., M.F.); NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (J.-k.J., C.J.T.); Ekam Imaging, Boston, MA (M.N.); and Departments of Pediatrics and Pathology, Columbia University Medical Center, New York, NY (T.G.D.). collerb@rockefeller.edu.

Abstract

OBJECTIVE:

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.

APPROACH AND RESULTS:

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.

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.

KEYWORDS:

blood platelets; myocardial infarction

Comment in

PMID:
25147334
PMCID:
PMC4180209
DOI:
10.1161/ATVBAHA.114.303724
[Indexed for MEDLINE]
Free PMC Article

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