INHIBITORS OF ATRIAL NATRIURETIC PEPTIDE CLEARANCE

THE ATRIAL NATRIURETIC PEPTIDE (ANP) HORMONAL SYSTEM, WHICH HAS AN IMPORTANT BIOLOGICAL ROLE IN FLUID AND ELECTROLYTE HOMEOSTASIS, REPRESENTS AN IMPORTANT NEW THERAPEUTIC TARGET FOR CARDIOVASCULAR DISEASE STATES. THIS RESEARCH IS BASED ON THE RECENT IDENTIFICATION OF A NOVEL MECHANISM FOR CLEARANCE OF ENDOGENOUS ATRIAL PEPTIDES THROUGH INTERACTION WITH SPECIFIC ANP BINDING SITES (C-ANP RECEPTORS) THAT DO NOT APPEAR TO MEDIATE ANY OF THE KNOWN BIOLOGICAL ACTIONS OFANP'S. ANP ANALOGS THAT BIND TO AND SATURATE C-ANP RECEPTORS CAUSE ENDOGENOUS ANP LEVELS TO INCREASE, ALLOWING THERAPEUTICALLY DESIRABLE RENAL AND BLOOD-PRESSURE-LOWERING EFFECTS TO BE OBSERVED. THIS STUDY WILL EXAMINE THE STRUCTURE-ACTIVITY RELATIONSHIPS OF C-ANP RECEPTOR-SPECIFIC LIGANDS FOR THE PURPOSE OF DEVELOPING INHIBITORS OF ANP CLEARANCE. THIS RESEARCH IS AIMED AT THE GENERATION OF A NEW CLASS OF ORALLYACTIVE, STABLE COMPOUNDS THAT HAVE THERAPEUTIC UTILITY IN TREATING HYPERTENSION, HEART FAILURE, AND RELATED EDEMATOUS STATES.