The Chemistry and Biology of Soluble Guanylate Cyclase Stimulators and Activators
Abstract
The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. Still today, NO‐donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long‐term treatment, and nonspecific effects, such as post‐translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme‐containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO‐independent manner, the so‐called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone Phase III clinical trials for different forms of pulmonary hypertension.
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sGC activators trigger catalytic activity independently of the redox state of the sGC heme or even in the absence of bound heme, working as heme analogs that replace the heme group and activate cGMP formation.
“sGC activators are compounds that can trigger the catalytic activity of sGC independently of the redox state of the sGC heme or even in the absence of bound heme. In general, these compounds work as heme analogs, replacing the heme group and triggering a similar conformational change to that of NO-bound heme in the native enzyme, thus activating cGMP formation (302).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [302]
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References 133 · Cited by 200
- Authors
- Follmann, M., Griebenow, N., Hahn, M. G., Hartung, I., Mais, F., Mittendorf, J., Schäfer, M., Schirok, H., Stasch, J., Stoll, F., & Straub, A.
- Affiliations
- Bayer (Germany) (DE)
- Corresponding author
- Follmann, Markus
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2013-08-20
- Volume
- 52
- Issue
- 36
- Pages
- 9442-9462
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2161209656
- Cited by
- 200
- References
- 133
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 12 · 2021: 19 · 2020: 17 · 2019: 18 · 2018: 18 · 2017: 23 · 2016: 19 · 2015: 26 · 2014: 14 · 2013: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- soluble guanylate cyclase, sGC stimulators, sGC activators, riociguat, nitric oxide, cyclic GMP, pulmonary hypertension, organic nitrates, vasodilators, cardiovascular disease
- MeSH terms
- Soluble Guanylyl Cyclase, Enzyme Activation, Guanylate Cyclase, Humans, Pyrazoles, Pyrimidines, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Enzyme Activators, Drug Discovery
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