NOVEL THERAPEUTIC AGENT FOR MYOCARDIAL INFARCTION

THE GOAL OF THIS RESEARCH IS TO DEVELOP A POTENT AND SPECIFIC PHARMACOLOGICALLY USEFUL ANTAGONIST TO THE LEUKOTRIENE B4 (LTB4) RECEPTOR FOR USE AS A NEW THERAPEUTIC AGENT IN MYOCARDIAL INFARCTION. LTB4 IS A LIPID MEDIATOR PRODUCED BY A VARIETY OF INFLAMMATORY CELLS VIA THE ARACHIDONIC ACID 5-LIPOXYGENASE PATHWAY. IT IS A POTENT ACTIVATOR OF LEUKOCYTE FUNCTIONS, INCLUDING AGGREGATION, ADHESION, CHEMOTAXIS, DEGRANULATION, AND SUPEROXIDE ANION GENERATION. ITS EFFECTS ARE BELIEVED TO BE RESPONSIBLE FOR LEUKOCYTE INFILTRATION FOLLOWING MYOCARDIAL INFARCTION WITH SUBSEQUENTPLUGGING OF MYOCARDIAL CAPILLARIES AND DAMAGE TO THE MYOCARDIUM. FUNCTIONALLY IMPORTANT RECEPTORS FOR LTB4 HAVE BEEN IDENTIFIED ON HUMAN POLYMORPHONUCLEAR LEUKOCYTES. THIS PROJECT WILL: (1) DESIGN AND SYNTHESIZE NOVEL LTB4 ANTAGONISTS BASED ON KNOWN LEAD COMPOUNDS THAT BIND TO THE LTB4 RECEPTOR, AND (2) EVALUATE THE NEW COMPOUNDS AS LTB4 ANTAGONISTS IN SEVERAL IN VITRO ASSAYS. THE COMPOUNDS DEVELOPED IN THESE STUDIES WILL GREATLY INCREASE KNOWLEDGE OF THE STRUCTURE-ACTIVITY RELATIONSHIPS FOR LTB4 RECEPTOR LIGANDS, WHICH MAY LEAD TO THE DISCOVERY OF NOVEL THERAPEUTIC AGENTS.