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

Abstract

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.

Novel strategies in nephrology: what to expect from the future?

“…Aldosterone synthase inhibitors, mainly the inhibitor of aldosterone synthase enzyme or CYP11B2, have been investigated for their potential role in the treatment of heart failure, hypertension and kidney diseases [ 132 , 133 ]. LCI699, the first orally administered aldosterone synthase inhibitor (ASI), has shown to lead a reduction in plasma aldosterone concentration along with an increase in plasma renin and deoxycortisol concentration [ 134 ].…”