SBIR-STTR Award

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.

Thesaurus Terms:
anticoagulant, biomimetics, heparin, inhibitor /antagonist, molecular weight, protamine, therapy design /development chemical stability, chemical structure function, dosage, intermolecular interaction, pharmacokinetics, salicylate, toxicology chemical synthesis, laboratory rat

LMWHs are being used with greater frequency to treat deep vein thrombosis, unstable angina, and acute pulmonary embolism, as well as thromboprophylaxis agents in a wide range of clinical situations including orthopedic surgery, high risk pregnancy, and cancer therapy. The most common complication of anticoagulation with LMWHs is hemorrhage. Many published clinical studies report 1% to 4% major (life-threatening) bleeding associated with LMWH therapy and there is a 5-fold increase in the overall death rate for acute coronary syndrome patients receiving anti- coagulant therapy that experience major bleeding. Although protamine is commonly used to neutralize UFH following coronary bypass surgery, it is unable to completely reverse the anticoagulant effects of LMWHs or fondaparinux. Therefore, there is a strong medical need for the development of a safe and effective antagonist for the LMWHs. The goal would be to develop an antidote that could rapidly reverse unwanted bleeding yet permit rapid resumption of anticoagulation therapy with a new dose of LMWH to restore thromboprophylaxis. 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. We propose to evaluate the suitability of current lead compounds as antagonists to LMWH and fondaparinux in preclinical efficacy and safety studies designed to identify clinical candidates. In addition, we propose to continue medicinal chemistry efforts in the salicylamide series and a newer series of arylamides to identify back-up compounds to substitute into the discovery program if problems are encountered with the current lead compounds.

Public Health Relevance:
Low molecular weight heparins (LMWHs) and the pentasaccharide, fondaparinux, 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 pentasaccharide or the low molecular weight heparins. We are developing safe and effective non-peptidic oligomers to neutralize the anti-coagulation properties of LMWH and fondaparinux.

Thesaurus Terms:
Adme Study; Absorption, Distribution, Metabolism, And Excretion Study; Acute; Adverse Experience; Adverse Event; Affect; Angina At Rest; Angina, Preinfarction; Animals; Anticoagulant Agents; Anticoagulant Drugs; Anticoagulants; Anticoagulation; Antidotes; Aortocoronary Bypass; Assay; Back; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Biomimetics; Bleeding; Blood Plasma; Blood Serum; Blood Erythrocyte; Blood Normocyte; Cancer Treatment; Cardiac; Cell Line; Cell Lines, Strains; Cellline; Chemicals; Chemistry; Chemistry, Pharmaceutical; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Phase Ii; Clinical Trials, Unspecified; Clotting; Coagulants; Coagulation; Coagulation Process; Common Rat Strains; Complement Activation; Complication; Coronary Artery Bypass; Coronary Artery Bypass Grafting; Coronary Artery Bypass Surgery; Dalteparin; Death Rate; Deep Vein Thrombosis; Deep-Venous Thrombosis; Derivation; Derivation Procedure; Development; Dorsum; Dose; Drug Kinetics; Drug Or Chemical Tissue Distribution; Electrophysiology; Electrophysiology (Science); Endothelial Cells; Enoxaparin; Enzymes; Erythrocytes; Erythrocytic; Exhibits; Fibrin; Fibroblasts; Frequencies (Time Pattern); Frequency; Goals; Hemorrhage; Heparin Antagonists; Heparin, Low-Molecular-Weight; High-Risk Pregnancy; Human; Human, General; In Vitro; Investigational New Drug Application; Kilogram; Lmwh; Lead; Life; Light; Lovenox; Low-Molecular-Weight Heparin; Lytotoxicity; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Mammals, Rats; Man (Taxonomy); Man, Modern; Marrow Erythrocyte; Medical; Medicinal Chemistry; Membrane Proteins; Membrane-Associated Proteins; Methods; Mimetics, Biological; Modeling; Molecular Interaction; Neurophysiology / Electrophysiology; Operation; Operative Procedures; Operative Surgical Procedures; Orthopedic Surgery Procedures; Patients; Pb Element; Peptides; Pharmaceutic Chemistry; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phase; Phase 2 Clinical Trials; Phase Ii Clinical Trials; Photoradiation; Plasma; Principal Investigator; Process; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Protamines; Protein Binding; Proteins; Protocols, Treatment; Publishing; Pulmonary Embolism; Rgm; Rat; Rattus; Receptor Protein; Red Blood Cells; Red Cell; Red Blood Corpuscule; Red Cell Of Marrow; Regimen; Reporting; Research; Research Design; Resistance; Reticuloendothelial System, Erythrocytes; Reticuloendothelial System, Serum, Plasma; S Period; S Phase; S Phase (Cell Cycle); Safety; Science Of Chemistry; Series; Serum; Serum, Plasma; Solutions; Structure; Study Type; Surface Proteins; Surgery, Orthopedic; Surgical; Surgical Interventions; Surgical Procedure; Synthesis Period; Synthesis Phase; Tedelparin; Testing; Therapeutic Index; Theriacs; Tissue Distribution; Toxic Effect; Toxicities; Treatment Protocols; Treatment Regimen; Treatment Schedule; Unstable Angina; Acute Coronary Syndrome; Animal Efficacy; Anticancer Therapy; Base; Blood Corpuscles; Blood Loss; Blood Thinner; Cancer Therapy; Clinical Investigation; Complement Pathway Regulation; Coronary Bypass; Cultured Cell Line; Cytotoxic; Cytotoxicity; Design; Designing; Dosage; Drug Development; Experience; Fondaparinux; Fragmin; Gene Product; Heavy Metal Pb; Heavy Metal Lead; Hemodynamics; Heparin Pentasaccharide; Improved; In Vitro Activity; In Vivo; Novel; Phase 2 Study; Phase 2 Trial; Phase Ii Trial; Physical Property; Preclinical Efficacy; Preclinical Evaluation; Programs; Protocol, Phase Ii; Public Health Relevance; Receptor; Resistant; Safety Study; Salicylamide; Scaffold; Scaffolding; Scale Up; Study Design; Study, Phase Ii; Surgery; Thrombopoiesis Inhibitor