title: RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction.
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.
  
  
  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.affiliation: 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.).
authors.forename: Jihong
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Spandana
authors.initials: S
authors.lastname: Vootukuri
authors.affiliation: 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.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Shang
authors.affiliation: 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.).
authors.forename: Ana
authors.initials: A
authors.lastname: Negri
authors.affiliation: 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.).
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: 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.).
authors.forename: Mark
authors.initials: M
authors.lastname: Nedelman
authors.affiliation: 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.).
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Diacovo
authors.affiliation: 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.).
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.affiliation: 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.).
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Coller
mesh_terms: D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016893:Carotid Stenosis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D002712:Chlorides; D004195:Disease Models, Animal; D004632:Emergency Medical Services; D005290:Ferric Compounds; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011744:Pyrimidinones; C000593083:RUC-4 compound; D013830:Thiadiazoles; D014841:von Willebrand Factor; C024555:ferric chloride
keywords: blood platelets; myocardial infarction