Citations 1
Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators
Sangaralingham, S. Jeson , Whig, Kanupriya , Peddibhotla, Satyamaheshwar , Kirby, R. Jason, Sessions, H, Maloney, Patrick , Hershberger, Paul, Mose-Yates, Heather, Hood, Becky , Vasile, Stefan , Pan, Shuchong, Zheng, Ye , Malany, Siobhan , Burnett, John C. , Maloney, Patrick R , Sangaralingham, S. Jeson
Proceedings of the National Academy of Sciences | December 20, 2021 | Volume: 118 | Issue: 52 | Pages: No page available
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.