Research Project
9410054
ABSTRACT Diapin Therapeutics LLC is a preclinical stage company committed to develop new antiplatelet agents for the treatment of acute coronary syndrome associated with diabetes patients. Patients with diabetes exhibit platelet hyper-reactivity and are at increased risks of adverse cardiovascular events. Clopidogrel is the most broadly used P2Y12 inhibitor to prevent arterial thrombosis. However clopidogrel has manifested clinical limitations of interindividual variability, delayed onset of action, and drug-drug interactions. These limitations are exacerbated in diabetes patients leading to elevated risks of ischemic complications. Although newer P2Y12 inhibitors such as prasugrel and ticagrelor have been shown to have better platelet inhibition, the risk of bleeding of these inhibitors is still significantly higher than that of clopidogrel therapy. Due to the epidemic growth of diabetes in the United States, the number of diabetes patients receiving antiplatelet therapy is projected to increase significantly in the next decade. Therefore there is a critical need to develop antiplatelet agents with improved benefit/risk ratio for diabetes patients. We have licensed exclusively an intellectual property from University of Michigan to develop ClopNPT, a novel conjugate of clopidogrel. Preliminary studies in animal models have shown that 1) ClopNPT rapidly (< 5 min) release the active metabolite (AM) of clopidogrel with high exposure, effectively preventing formation of occlusive arterial thrombi. 2) ClopNPT at the effective dose to inhibit occlusive thrombi does not increase bleeding. 3) Release of the AM from ClopNPT requires glutathione (GSH) only, and not CYP enzyme that is the main contributor to the clinical limitations of clopidogrel. Based on these data, we hypothesize that development of ClopNPT that has eliminated the clinical limitations of clopidogrel is an effective strategy to optimize the benefit/risk ratios for antiplatelet therapy in patients with diabetes. The aim of this proposal is to evaluate clinical risk of ClopNPT by comparing the efficacy and safety with those of clopidogrel, ticagrelor, and prasugrel in a rabbit arterial model of thrombosis. We will determine the time to occlusion following ferric chloride induced vascular injury as well as tongue bleeding time. This study will provide significant information whether ClopNPT is able to reduce the risks of bleeding, which allows us to conduct preclinical studies required for application of Investigational New Drug.
