Thrombostatin In The Folts Model for Coronary Thrombosis

DESCRIPTION (Applicant's Description Verbatim): The hypothesis of this proposal is that a thrombin inhibitor that selectively interferes with platelet activation will be an important therapeutic agent in the management of acute coronary syndromes. Thromgen, Inc. is developing a class of agents called thrombostatin as antithrombin, anti-platelet drugs to be used for heart attacks and interventional cardiovascular procedures. Thrombostatin prevents a-thrombin from activating platelets. It is a bifunctional inhibitor that weakly interacts with thrombin' s active site and more tightly interacts with thrombin's receptor, protease-activated receptor 1 (PAR 1). Thrombostatin is a novel platelet-selective thrombin inhibitor. The specific aims of this proposal are as follows: Specific Aim #1: Studies will be done to prepare more potent and selective inhibitors of thrombin activation of PAR1 by empiric synthesis and rational drug design. Specific Aim #2: The antithrombotic ability of thrombostatin and platelet glycoprotein IIb/IIIa antagonists will be compared in dogs. These investigations will result in the development of a novel class of platelet-selective thrombin inhibitors to prevent arterial thrombosis. These investigations also will result in a new therapeutic approach to the management of patients with acute coronary syndromes. PROPOSED COMMERCIAL APPLICATION: Not Available