Unfractionated heparin (UFH) and the low molecular weight heparins (LMWHs) are widely used anti-coagulants employed in a number of clinical and surgical applications. Common adverse events associated with the use of heparin as anti-coagulant therapy are bleeding and heparin-induced thrombocytopenia. Protamine, a small arginine-rich protein, is an effective antagonist that is used clinically to neutralize the anti-coagulant effects of UFH, but presently there are no effective antagonists for the LMWHs. Protamine reversal of heparin activity can cause a number of unwanted hematological and hemodynamic side effects. Therefore, there is significant clinical need for the development of safer protamine alternatives for the effective neutralization of the anti-coagulant function of heparin. Substantial additional clinical benefit would be achieved if the protamine substitute could also effectively and safely reverse the anti-coagulant effects of the LMWHs. A number of protein and peptide-based strategies to mimic protamine and protamine function have been pursued to develop a safe and efficacious protamine substitute but with very limited success. As an alternate strategy to the use of peptides as protein mimics, we are developing series of non-peptidic oligomers with well-defined secondary or tertiary structures to serve as novel templates for the design of compounds targeting specific protein-protein and protein-membrane interactions. These oligomers have many advantages over peptides: relatively smaller size which increases stability and enhances tissue distribution, ease of synthesis, resistance to proteolytic degradation, and suitability for medicinal chemistry approaches to fine-tune their physical properties and optimize potency and safety. We have utilized this strategy to design small oligomers that strongly interact with UFH and LMWH and antagonize their anti-coagulation properties. A preliminary library screen and limited chemical optimizations have identified presumptive anti-UFH lead compounds in two oligomer series. One of the compounds in the salicylamide series (PMX60054) also displays potent in vitro activity against some of the LMWHs. Initial animal studies have shown that PMX60054 has comparable potency and efficacy to protamine in neutralizing heparin activity in vivo. The Phase 1 research program hast two goals: 1) Synthesize and test additional salicylamides having in vitro activities suitable for moving forward into animal efficacy and safety studies as back-up compounds to PMX60054 and, 2) Evaluate the efficacy and safety of PMX60054 and/or back-up salicylamides in pilot animal studies to identify a discovery lead compound with a superior therapeutic index versus protamine suitable for further development Unfractionated heparin (UFH) and the low molecular weight heparins (LMWHs) are widely used anti-coagulants employed in a number of clinical and surgical applications. Bleeding complications are common adverse events associated with anti-coagulant therapy. Protamine is an effective antagonist of UFH but presently there are no effective antagonists for the LMWHs. Protamine reversal of UFH activity can also cause a number of unwanted side effects including reductions in heart rate and blood pressure. We are developing non-peptidic oligomers as substitutes for protamine to safely and effectively neutralize the anti-coagulation properties of UFH and potentially the LMWHs. [unreadable] [unreadable] [unreadable]