Discovery of BAY 94‐8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases

TLDR

Aldosterone damages kidneys, vessels, and heart, and blocking its mineralocorticoid receptor is a proven therapy, but existing steroidal antagonists lack selectivity or potency. The study aimed to discover nonsteroidal MR antagonists that overcome the liabilities of steroidal drugs. An extended structure‑activity‑relationship study began with cyano‑1,4‑dihydropyridines identified by high‑throughput screening. This led to BAY 94‑8862, a potent, selective, orally available nonsteroidal MR antagonist now in phase II trials.

Abstract

Abstract Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano‐1,4‐dihydropyridines that were identified by high‐throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94‐8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.