MCUF-651

MCUF-651 is a positive allosteric modulator (PAM) of the guanylyl cyclase A receptor (GC-A).¹ It induces the production of cGMP in the presence (EC₅₀ = 0.45 µM) but not the absence of atrial natriuretic peptide (ANP) in HEK293 cells expressing human GC-A. MCUF-651 is selective for GC-A over GC-B in HEK293 cells expressing the human receptors at 10 µM. It binds to the GC-A extracellular domain (K_d = 397 nM) and enhances the binding of ANP to the GC-A extracellular domain in cell-free assays. MCUF-651 (1-10 µM) enhances ANP-induced production of cGMP in primary human renal proximal tubular cells, visceral adipocytes, and cardiomyocytes. It also inhibits TGF-ß1-induced hypertrophy of primary human cardiomyocytes when used in combination with ANP. MCUF-651 induces cGMP production in GC-A-expressing HEK293 cells incubated with plasma isolated from patients with hypertension or heart failure.

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1. Sangaralingham, S.J., Whig, K., Peddibhotla, S., et al. Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators. Proc. Natl. Acad. Sci. USA 118(52), e2109386118 (2021).