Whig, Kanupriya

Significance The particulate guanylyl cyclase A receptor (GC-A), via its endogenous cardiac-derived hormones atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), plays a pivotal role in maintaining intravascular volume, arterial pressure, cardiovascular structure, function, and, more recently, metabolic homeostasis. As such, therapies to potentiate GC-A signaling via peptide augmentation have yielded promising results in clinical trials. A major breakthrough in GC-A therapeutics would be a small molecule that sensitizes the GC-A receptor to endogenous ANP or BNP, which to date does not exist. Here, we report the development of an orally bioavailable, small molecule positive allosteric modulator of GC-A that exhibits therapeutic activity in human hypertension and heart failure ex vivo.