The discovery of the sGC stimulators and sGC activators provided valuable tools to elucidate NO-sGC signalling and opened novel pharmacological opportunities in cardiovascular indications and beyond. The first in class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO but also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem-free form of sGC. Substantial research efforts ameliorated the first-generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical phase II for chronic kidney disease and diabetic retinopathy. Here we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential.
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