ChemMedChem, 2012-08, Vol.7 (8), p.1385-1403
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.
MR activation kept at BAY: Inappropriate activation of the mineralocorticoid receptor by aldosterone or cortisol contributes to the development of cardiovascular diseases. BAY 94‐8862, antagonizing these effects, was identified in a lead optimization program and is currently being investigated in a phase II clinical trial for the treatment of chronic heart failure patients with renal impairment.
Animals ; BAY 94-8862 ; Binding Sites ; cardiorenal disease ; Care and treatment ; Chronic Disease ; Computer Simulation ; Drug Evaluation, Preclinical ; Heart failure ; Heart Failure - complications ; Heart Failure - drug therapy ; Humans ; Kidney Diseases - complications ; Kidney Diseases - drug therapy ; Mineralocorticoid Receptor Antagonists - chemical synthesis ; Mineralocorticoid Receptor Antagonists - chemistry ; Mineralocorticoid Receptor Antagonists - therapeutic use ; MR antagonists ; Naphthyridines - chemical synthesis ; Naphthyridines - chemistry ; Naphthyridines - therapeutic use ; natriuresis ; Nitriles ; Potassium - urine ; Protein Structure, Tertiary ; Rats ; Receptors, Mineralocorticoid - chemistry ; Receptors, Mineralocorticoid - metabolism ; Sodium - urine ; Spironolactone ; Steroids
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