Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
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.
Bayer Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal, Germany. lars.baerfacker@bayer.com
Lars
L
Bärfacker
Alexander
A
Kuhl
Alexander
A
Hillisch
Rolf
R
Grosser
Santiago
S
Figueroa-Pérez
Heike
H
Heckroth
Adam
A
Nitsche
Jens-Kerim
JK
Ergüden
Heike
H
Gielen-Haertwig
Karl-Heinz
KH
Schlemmer
Joachim
J
Mittendorf
Holger
H
Paulsen
Johannes
J
Platzek
Peter
P
Kolkhof
D000818:Animals; D001665:Binding Sites; D002908:Chronic Disease; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy*; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011188:Potassium / Q000652:urine; D017434:Protein Structure, Tertiary; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000378:metabolism; D012964:Sodium / Q000652:urine
D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; D018161:Receptors, Mineralocorticoid; C576501:finerenone; D012964:Sodium; D011188:Potassium