Design, synthesis, and evaluation of naphthalidinamide analogues as nonsteroidal mineralocorticoid receptor antagonists

Inappropriate overactivation of the mineralocorticoid receptor by the steroid hormones aldosterone or cortisol contributes to the development of cardiovascular diseases. The new mineralocorticoid receptor antagonist can directly block mineralocorticoid receptor overactivation, inhibit inflammation and profibrotic gene expression, thereby reducing chronic kidney disease progression and cardiovascular risk, achieving dual benefits for both kidney and heart. Antergy of mineralocorticoid receptor is a proven therapeutic concept for the management of chronic kidney disease and type 2 diabetes associated diseases. Using finerenone (BAY 94-8862) as an inspiration, several novel naphthalidinamide analogues were designed, synthesized and their biological activities were determined as nonsteroidal mineralocorticoid receptor antagonists. In vitro results showed that A2 (IC 50 = 30.3 nM) and B (IC 50 = 5.6 nM) exhibited significant antagonistic activities against mineralocorticoid receptor. Among them, compound B showed the most potent antagonistic activity against mineralocorticoid receptor cells which was much superior to the control compound BAY-94-8862 (IC 50 = 28.1 nM). Besides, the two potent compounds showed promising (>170-fold) selectivity over the glucocorticoid receptor, androgen receptor and progesterone receptor. Furthermore, they displayed rapid metabolic profiles in human, dog, monkey, rat, and mouse liver microsomes than the control compound BAY-94-8862 . These results highlighted the great potential compound B to become a promising mineralocorticoid receptor antagonist for cardiovascular disease.