Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

Overactivation
of the mineralocorticoid receptor (MR) is involved
in many diseases, such as hypertension, kidney disease, and heart
failure. Thus, MR antagonists (MRAs) are expected to be beneficial
to patients with these diseases. In order to identify novel nonsteroidal
MRAs that overcome the issues of already marketed steroidal MRAs,
we searched for new compounds guided by our hypothesis that T-shaped
compounds with a hydrophobic core structure, two polar functional
groups at both extremities able to interact with MR, and a bulky substituent
that can interfere with the folding of the C-terminal helix 12 may
exhibit antagonist activity toward MR. We discovered that the novel
1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995)
acted as a highly selective and potent nonsteroidal MRA. Apararenone
exhibited a more potent antihypertensive and organ-protective activity
than steroidal MRA eplerenone in a primary aldosteronism rat model
obtained by infusing aldosterone in uninephrectomized rats.