Ruc-4

Abstract

Objective Treatment of myocardial infarction (MI) within the first 1–2 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 (IM) by autoinjector to facilitate its use in the pre-hospital 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 vs 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. IM injection of RUC-4 in non-human 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 4.5–24 hours. Conclusions RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a pre-hospital therapy of MI, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

Integrin-based therapeutics: biological basis, clinical use and new drugs

“…Recently, however, Coller and colleagues identified an αIIbβ3-selective compound from a high-throughput drug screen that does not induce a detectable conformational change in αIIbβ3 when it binds to the RGD binding site in the receptor. Subsequent structure-based drug design and development of a water-soluble congener, RUC-4, demonstrated a sub-micromolar IC 50 for ADP-induced platelet aggregation, both in vitro and after intramuscular administration to non-human primates 56 . RUC-4 may be further evaluated for potential administration to patients with acute coronary syndromes in the pre-hospital setting, because the drug could be available in a formulation for intramuscular administration, a clear advantage over intravenous αIIbβ3 antagonists in an ambulance setting.…”

αIIbβ3 binding to a fibrinogen fragment lacking the γ-chain dodecapeptide is activation dependent and EDTA inducible

“…, 59 adhered less well compared with untreated cells ( Figure 3C). The adhesion of aIIb(FF)b3-HEK to 'D98' was inhibited by soluble 'D98' (1.0 mg/mL), but not by soluble fibrinogen (1.5 mg/mL) ( Figure 3D).…”

A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3

“…RUC-2 and RUC-4 were developed following RUC-1. Currently RUC-4 is under development for the prehospital therapy of ST segment elevated myocardial infarction [31, 32]. Ur-3216/2922, binding to α IIb D224 and not engaging the MIDAS metal ion, is a high affinity α IIb β 3 antagonist without ligand-induced binding site (LIBS) expression.…”