Soluble guanylate cyclase stimulators and activators: Chemistry, biology, and therapeutic advances.

The discovery of soluble guanylate cyclase (sGC) stimulators and activators has provided invaluable tools for elucidating nitric oxide (NO)-sGC signaling and has opened up novel therapeutic opportunities for cardiovascular diseases and beyond. In recent years, sGC modulators have garnered widespread attention as promising agents for diseases such as pulmonary hypertension, heart failure, chronic kidney disease, and diabetic retinopathy-with sGC stimulators and sGC activators emerging as key research focuses in this field. Although first-in-class sGC stimulators (e.g., riociguat, vericiguat) and activators (e.g., cinaciguat) have advanced into clinical use or development, most subsequent candidates continue to be refined to optimize efficacy, safety, and target selectivity. This review provides a comprehensive and systematic exploration of sGC stimulators and sGC activators in the context of disease therapy. Specifically, these small molecules are classified and elaborated based on their mechanisms of action, structural characteristics, and development trajectories; for each category, the binding modes, structural features, and pharmacological activities of representative compounds are analyzed in detail, while their inherent advantages and limitations are critically evaluated. Collectively, this review offers valuable insights and guidance for the future research and development of safer, more effective, and more precisely targeted sGC modulators.