Volume 7 Supplement 1

3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

Design and synthesis of the first NO- and haem-independent sGC activator BAY 58–2667 for the treatment of acute decompensated heart failure

  • Michael G Hahn1Email author,
  • Cristina Alonso-Alija1,
  • Friederike Stoll1,
  • Markus Heil1,
  • Joachim Mittendorf1,
  • Karl-Heinz Schlemmer1,
  • Frank Wunder1 and
  • Johannes-Peter Stasch1
BMC Pharmacology20077(Suppl 1):P25

https://doi.org/10.1186/1471-2210-7-S1-P25

Published: 25 July 2007

Soluble guanylate cyclase (sGC) is a signal-transduction enzyme activated by nitric oxide (NO) and plays a key role in a variety of physiological processes such as vasodilatation, antiaggregation, antiproliferation and neuronal signaling as well as in a variety of disorders of these functions. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules and lack of response and the development of tolerance [1, 2]. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages.

High throughput screening led to the identification of a series of dicarboxlic acids as potent sGC activators. Lead structure 1 showed promising in vitro potency (sGC overexpressing CHO-cells and relaxation of precontracted rabbit arteria saphena rings) and haemodynamic effects in anaesthetized rats (Fig. 1). Extensive chemical derivatization resulted in conclusive structure activity relationships, which will be presented. Eventually, optimization led to the discovery of BAY 58–2667, a highly potent sGC activator which is currently in clinical trials in patients for the treatment of acute decompensated chronic heart failure.
Figure 1

Discovery of sGC activators via ultra-high throughput screening using sGC-overexpressing CHO cell lines.

Authors’ Affiliations

(1)
Pharma Research Center, Bayer HealthCare AG

References

  1. Stasch JP, Schmidt P, Alonso-Alija C, Apeler H, Dembowsky K, Haerter M, Heil M, Minuth T, Perzborn E, Pleiss U, Schramm M, Schroeder W, Schröder H, Stahl E, Steinke W, Wunder F: NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol. 2002, 136: 773-783. 10.1038/sj.bjp.0704778.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HHHW, Stasch JP: NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nature Reviews Drug Discovery. 2006, 5: 755-768. 10.1038/nrd2038.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Hahn et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

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