The chemistry and biology of soluble guanylate cyclase stimulators and activators

Angew Chem Int Ed Engl. 2013 Sep 2;52(36):9442-62. doi: 10.1002/anie.201302588. Epub 2013 Aug 20.


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.

Keywords: drug discovery; guanylate cyclase; medicinal chemistry; riociguat; structural biology.

Publication types

  • Review

MeSH terms

  • Drug Discovery
  • Enzyme Activation / drug effects
  • Enzyme Activators / pharmacology*
  • Guanylate Cyclase / metabolism*
  • Humans
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction
  • Soluble Guanylyl Cyclase


  • Enzyme Activators
  • Pyrazoles
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • riociguat