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pp 1-39 | Cite as

Soluble Guanylate Cyclase Stimulators and Activators

  • Peter SandnerEmail author
  • Daniel P. Zimmer
  • G. Todd Milne
  • Markus Follmann
  • Adrian Hobbs
  • Johannes-Peter Stasch
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

Graphical Abstract

Keywords

cGMP Cyclic guanosine monophosphate Nitric oxide sGC sGC activator sGC stimulator Soluble guanylyl cyclase 

Notes

Acknowledgments

The authors would like to thank Christian Meier, Kelly Lewis, and Shalini Murali at Bayer and Jennifer Chickering, Albert Profy, Emmanuel Buys, Joon Jung, Paul Renhowe, Yueh-tyng Chien, Regina Graul, and Chris Winrow at Ironwood for contributions to and critical reading of the manuscript.

Conflict of Interest

GTM and DPZ are employees of Ironwood Pharmaceuticals, and MF, PS, and JPS are employees of Bayer AG Pharmaceuticals.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Peter Sandner
    • 1
    • 2
    Email author
  • Daniel P. Zimmer
    • 3
  • G. Todd Milne
    • 3
  • Markus Follmann
    • 1
  • Adrian Hobbs
    • 4
  • Johannes-Peter Stasch
    • 1
    • 5
  1. 1.Bayer AG, Pharmaceuticals R&D, Pharma Research CenterWuppertalGermany
  2. 2.Department of PharmacologyHannover Medical SchoolHannoverGermany
  3. 3.Ironwood PharmaceuticalsCambridgeUSA
  4. 4.Barts and the London School of Medicine and Dentistry QMULLondonUK
  5. 5.Institute of PharmacyUniversity Halle-WittenbergHalleGermany

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