Novel allosteric modulators of guanylyl cyclase A activity

Natriuretic peptides are important regulators in the cardiovascular and renal system with pleiotropic effects. Atrial (ANP) and brain natriuretic peptide (BNP) activate the natriuretic peptide receptor A (NPR-A), causing production of cyclic guanosine monophosphate (cGMP). Various designer natriuretic peptides have been developed and investigated for treatment of heart failure and hypertension, but their major limitations are that they have short half-life and are not available for oral administration. Our novel approach is to find small molecular drugs to help and treat patients with cardiovascular diseases (CVDs), through targeting NPR-A. We have identified small molecular allosteric enhancers of NPR-A, which increase the efficacy and potency of BNP and ANP in their ability to activate NPR‐A and generate cGMP. These compounds were characterized as NPR-A-selective allosteric enhancers, and their activity is dependent on one unique amino acid in NPR-A. Finally, a pre-study in an animal model was performed to test the formulation and assure the lead compound is well tolerated by the animals.