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

  1. Dr. Lars Bärfacker1,*,
  2. Dr. Alexander Kuhl1,
  3. Prof. Dr. Alexander Hillisch1,
  4. Dr. Rolf Grosser1,
  5. Dr. Santiago Figueroa-Pérez1,
  6. Dr. Heike Heckroth1,
  7. Adam Nitsche1,
  8. Dr. Jens-Kerim Ergüden1,
  9. Dr. Heike Gielen-Haertwig1,
  10. Dr. Karl-Heinz Schlemmer2,
  11. Prof. Dr. Joachim Mittendorf1,
  12. Dr. Holger Paulsen1,
  13. Dr. Johannes Platzek3,
  14. Dr. Peter Kolkhof4

Article first published online: 12 JUL 2012

DOI: 10.1002/cmdc.201200081

Issue

ChemMedChem

ChemMedChem

Volume 7, Issue 8, pages 1385–1403, August 2012

Additional Information

How to Cite

Bärfacker, L., Kuhl, A., Hillisch, A., Grosser, R., Figueroa-Pérez, S., Heckroth, H., Nitsche, A., Ergüden, J.-K., Gielen-Haertwig, H., Schlemmer, K.-H., Mittendorf, J., Paulsen, H., Platzek, J. and Kolkhof, P. (2012), Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases. ChemMedChem, 7: 1385–1403. doi: 10.1002/cmdc.201200081

Author Information

  1. 1

    Bayer Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal (Germany)

  2. 2

    Bayer Pharma AG, DMPK, 42096 Wuppertal (Germany)

  3. 3

    Bayer Pharma AG, Chemical Development, 42096 Wuppertal (Germany)

  4. 4

    Bayer Pharma AG, Cardiology Research, 42096 Wuppertal (Germany)

*Bayer Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal (Germany)

Publication History

  1. Issue published online: 31 JUL 2012
  2. Article first published online: 12 JUL 2012
  3. Manuscript Revised: 11 JUN 2012
  4. Manuscript Received: 9 FEB 2012

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Keywords:

  • BAY 94-8862;
  • cardiorenal disease;
  • heart failure;
  • MR antagonists;
  • natriuresis

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.

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