There are 3 categories of antiplatelet agents approved in the U.S.: aspirin, which was serendipitously found to have antiplatelet effects; P2Y12 antagonists that originated with the discovery of the antiplatelet effects of ticlopidine in a pharmaceutical screen for antiplatelet effects; and αIIbβ3 antagonists which were the first antiplatelet agents developed from a rational understanding of platelet physiology. Currently, advances in the structural biology of integrin αIIbβ3 have opened up the opportunity to develop improved antagonists for specific medical indications, including pre-hospital therapy of myocardial infarction. Approximately 50% of the deaths from heart attacks now occur in the pre-hospital period, but there has been relatively little improvement in pre-hospital therapy compared to the dramatic advances in therapy after arriving to the hospital. Therapy with current αIIbβ3 antagonists (along with aspirin) soon after symptom onset can abort the progression of thrombotic myocardial ischemia to irreversible cardiac damage and decrease mortality. However, the current αIIbβ3 antagonists all must be administered intravenously as a continuous infusion, a major disadvantage for pre-hospital therapy. Moreover, current agents all are associated with thrombocytopenia and potentially paradoxical activation of the receptor. Based on crystallographic structural studies of αIIbβ3, RUC-4 was designed to be specific for αIIbβ3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the β3 subunit induced by current αIIbβ3 antagonists patterned on the R(K)GD sequence that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4 was also designed to have high solubility (~60-80 mg/ml) so that the likely human dose (~1 mg/kg) can be administered in ~1 ml by autoinjector. Based on studies in mice and non-human primates, RUC-4 is rapidly absorbed after IM injection. In non-human primates, platelet aggregation was eliminated within 15 minutes after a single 0.27 ml IM dose of 1.93 mg/kg with partial return of platelet aggregation after ~4.5 hours. A lower dose (0.47 ml; 1 mg/kg) produced partial inhibition of aggregation at 15 minutes, complete inhibition at 30 minutes, and partial return of aggregation at 2 hours. The platelet counts were unchanged in all three animals. In other studies in non-human primates, RUC-4 was well tolerated when co-administered with aspirin at doses up to 32 mg/kg. We are currently planning additional studies to support an IND for a Phase 1 study of RUC-4 in humans.

 PROGRESS IN NEUROSCIENCE

PINS

Seminar Series of the Brain & Mind Research Institute

Weill Cornell Medical College (WCMC) &

The Graduate Program in Neuroscience of WCMC and Sloan Kettering Institute

Thursday, 6/5/14, 4 PM, coffee at 3:45 PM

Weill Auditorium

Antiplatelet Therapy: From Serendipity, to Random Screening, to Rational Molecular Design

Barry S. Coller, M.D. David Rockefeller Professor of Medicine

Physician-in-Chief, The Rockefeller University Hospital

Abstract:

   

Recent relevant publications: Zhu J, Zhu J, Negri A, Provasi D, Filizola M, Coller BS, Springer TA. The closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specific antagonist that does not induce opening. Blood.116:5050-5059, 2010. PMCID: PMC3012599

Coller, B.S. Historical perspective and future directions in platelet research. J Thromb Haemostas, 9(Suppl 1):374-395, 2011. PMCID: PMC3163479