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

Therapeutic Approaches
DMPK

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.

Authors

Li, Jihong; Vootukuri, Spandana; Shang, Yi; Negri, Ana; Jiang, Jian-Kang; Nedelman, Mark; Diacovo, Thomas G; Filizola, Marta; Thomas, Craig; Coller, Barry S;

Keywords

  • 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

External Links