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

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


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • Animals
  • Binding Sites
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Carotid Stenosis / blood
  • Carotid Stenosis / chemically induced
  • Carotid Stenosis / prevention & control*
  • Chlorides
  • Disease Models, Animal
  • Emergency Medical Services*
  • Ferric Compounds
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / metabolism
  • Fibrinolytic Agents / pharmacokinetics
  • Fibrinolytic Agents / pharmacology*
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Dynamics Simulation
  • Myocardial Infarction / blood
  • Myocardial Infarction / drug therapy*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Platelet Glycoprotein GPIIb-IIIa Complex / chemistry
  • Platelet Glycoprotein GPIIb-IIIa Complex / genetics
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Protein Binding
  • Protein Conformation
  • Pyrimidinones / chemistry
  • Pyrimidinones / metabolism
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / pharmacology*
  • Solubility
  • Thiadiazoles / chemistry
  • Thiadiazoles / metabolism
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / pharmacology*
  • Thrombosis / blood
  • Thrombosis / chemically induced
  • Thrombosis / prevention & control*
  • von Willebrand Factor / genetics
  • von Willebrand Factor / metabolism


  • Chlorides
  • Ferric Compounds
  • Fibrinolytic Agents
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Pyrimidinones
  • RUC-4 compound
  • Thiadiazoles
  • von Willebrand Factor
  • ferric chloride