A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

C-type
natriuretic peptide (CNP) is involved in the regulation
of vascular homeostasis, which is at least partly mediated through
agonism of natriuretic peptide receptor C (NPR-C), and loss of this
signaling has been associated with vascular dysfunction. As such,
NPR-C is a novel therapeutic target to treat cardiovascular diseases.
A series of novel small molecules have been designed and synthesized,
and their structure–activity relationships were evaluated by
a surface plasmon resonance binding assay. The biological activity
of hit compounds was confirmed through organ bath assays measuring
vascular relaxation and inhibition of cAMP production, which was shown
to be linked to its NPR-C activity. Lead compound 1 was
identified as a potent agonist (EC50 ∼ 1 μM)
with promising in vivo pharmacokinetic properties.