Heart attack and related thrombotic diseases are among the leading causes of death in America. The American Heart Association estimates that as many as 1.5 million people in the U.S. will suffer heart attacks this year, with more than one-third resulting in death. In addition it is estimated that 1/2 million Americans suffer a stroke per year with about 80% of all stroke caused by blood clots. Thrombosis, septic shock and a variety of related forms of diseases are associated with, and result from, the activation of one or more of the coagulation protease cascade pathways. In Phase I, we propse to develop new peptidyl inhibitors of thrombin and factors VIIa and Xa, enzymes involved in the initiation of the extrinsic coagulation pathway, by the design and synthesis of a unique class of peptide analogs containing conformationally constrained boroamino acids. These novel inhibitors will be tested for potency and specificity. In Phase II, we intend to develop therapeutic molecules based on the active peptides discovered in Phase I. Molecular modeling and peptidomimetic techniques will be used to optimize their activity against their specific targets. Additionally, the availability of active constrained amino acid mimics will allow the design and synthesis of potential non-peptide, small molecule inhibitors of these enzymes.
