Enhancing Thrombostatin's Oral Delivery

DESCRIPTION (provided by applicant): The long term objective of the project is to develop an orally bioavailable drug for treatment of individuals with acute coronary syndromes (ACS) and also individuals whose cancer is influenced by the mitogenic effects of thrombin. Current therapy for the acute coronary syndrome is a combination of anticoagulant/antiplatelet agents and percutaneous transluminal coronary angioplasty. Many of the agents routinely used for anticoagulant/antiplatelet activity, such as heparin, are administered intravenously. Other oral agents attack specific platelet targets like the ADP receptor (clopidogrel) or platelet cyclooxygenase (aspirin). Moreover, in recent years, thrombin, a procoagulant protein, has also been recognized as a potent mitogen and its inhibition may influence cancer growth and metastasis. We are aiming to develop an orally available thrombin inhibitor and thrombin receptor activation antagonist. Presently, we have a lead compound undergoing toxicology studies for an IND application for intravenous use in man. This compound is based upon a novel series of pentapeptide compounds consisting of D and synthetic amino acids derived from the ACE breakdown product of bradykinin. These compounds, collectively termed "Thrombostatins," show potential as inhibitors of thrombin and antagonists of thrombin activation of platelet protease activated receptors 1 and 4 (PAR1 and 4). In the current proposal, we aim to improve the oral bioavailability of the latest generation of Thrombostatins by chemical modification of the peptide structure in order to make the compound more lipophilic. The specific aims of this Phase 1 SBIR proposal are: Specific Aim #1: Synthesis of Masked Thrombostatin Analogs: We will synthesize a series of analogs of our lead Thrombostatin analog in order to reduce the charge and increase the hydrophobicity on the peptide. Specific Aim #2: Evaluation of Intestinal Absorption of the Thrombostatin Analogs: The new Thrombostatin analogs will be evaluated for intestinal stability and enhanced oral transport. Specific Aim #3: Testing of the Thrombostatin Analogs for oral anti-thrombosis activity: Testing of the novel oral Thrombostatin analogs for anti-thrombin activity in vitro and in vivo. The proposed work aims to advance the gastrointestinal bioavailability of Thrombostatin analogs to create an orally available thrombin and thrombin receptor activation antagonist for acute coronary syndrome and cancer therapy. This project specifically involves the development of a new oral drug to treat heart attacks and cancer.