The atrial natriuretic peptide (ANP) hormonal system, which has an important biological role in fluid and electrolyte homeostasis, represents and important new therapeutic target for cardiovascular disease states. The proposed research is based on the identification of a mechanism of clearance of endogenous atrial peptides through interaction with specific ANP clearance receptors (ANP C-receptors). During Phase I, a series of small ANP C-receptor specific analogs were generated. By binding to end saturating ANP C-receptors, these compounds cause endogenous ANP levels to increase and produce therapeutically desirable renal and cardiovascular effects. During Phase II investigations, the relationship between the pharmacodynamic and pharmacokinetic properties of these ANP C-receptor compounds will be established. The in vitro metabolic stability and intestinal permeability of the compounds will also be studied. These data should help in the identification of specific physical and biochemical properties of the molecules to direct subsequent synthetic efforts. In addition, some compounds will be evaluated in both oral and nasal formulations. It is anticipated that one or two ANP C-receptor compound formulations will emerge from these studies as candidates for further development and clinical testing in humans.
