An important unmet medical need is for an effective, orally bio-available anticoagulant. The current limitation of both standard heparin and low molecular weight heparin is that they must be administered intravenously or subcutaneously. The use of Coumadin (warfarin) is limited by its very narrow therapeutic index and it's propensity to elicit complications of uncontrolled bleeding. We propose to address this gap in current anticoagulant therapy by creating derivatives of low molecular weight heparin with a natural surfactant as a covalent molecular component. This will create an antithrombotic agent of choice available as an orally absorbable compound. The proposed approach is that of using unique bile acid derivatives as prodrug that will serve as carriers of heparin. We will prepare three unique derivatives of low molecular weight heparin. The covalent association of a surfactant moiety with the heparin molecule will enhance the permeability of the heparin molecule at specific and defined sites and will render it orally absorbable. We previously prepared orally active heparin derivatives at the C-17 carboxyl position of bile acids to yield modestly active conjugate. Because the C-17 position of the bile acid contributes to intestinal absorbance, the bile acid could not be fully absorbed. We now propose a unique synthetic methodology converting the C-3 OH of the bile acid molecule - which is not directly involved in intestinal absorbability - to reactive linkage moieties (NH2 or COOH), to provide target sites for three potentially absorbable heparin derivatives. Our derivatives are innovative and unique and are not dependent on the carboxyl group of the bile acid for ligation. The compounds prepared in this program will be tested in small animals to establish efficacy and bioavailability. Ultimately, we hope that this class of derivatives will be useful clinically in formulations for the long-term prophylaxis or treatment of chronic coronary syndromes, treatment in stroke, and other cardiovascular indications. An orally active heparin derivative that is non-toxic can become a major pharmaceutical for maintenance therapy of thrombophlebitis and generally for the treatment of hypercoagulable states associated with a multiplicity of conditions.
There is a need for an orally absorbable anticoagulant for human that requires minimal dosing, has sustained action, and whose anticoagulant action is readily reversible and at the same time has an economic benefit by minimizing hospitalizations and attendant costs especially propitious at this time. Although our program as presented appears ambitious for the allotted time period, we recognize that our effort concentrates on a feasibility study and we propose to demonstrate the activity of an oral derivative. The program is designed to establish activity permitting us to fully develop the compounds in a Phase II study. ? ? ?
