cGMP Pathway: Core Target for Precision Cardiovascular Drug Development

Most existing drugs for heart failure and pulmonary hypertension merely ease symptoms rather than treat root causes. The cGMP signaling pathway offers a mechanism-based drug development strategy and gains growing industry focus.Researchers have defined the term "cGMPopathy". Chronic cardiovascular diseases such as coronary heart disease and hypertension arise from insufficient cGMP synthesis or excessive cGMP breakdown.Guanylate cyclases produce cGMP, while various PDE enzymes degrade it in specific cell regions. Their dynamic balance supports vasodilation and anti-myocardial fibrosis protection.

There are two major drug development directions. The first is sGC agonists such as vericiguat, which boost cGMP production and reduce heart failure hospitalization risks. The second is PDE inhibitors that block cGMP degradation.ARNI and natriuretic peptide drugs also raise cGMP levels by stabilizing endogenous natriuretic peptides.However, PDE and GC subtypes act in tissue-specific ways. Target activity varies significantly between humans and rodents, so monotherapy cannot suit all patients.

The industry prioritizes network pharmacology-based combination therapy. Combined with cGMP-related biomarkers, doctors can screen matching patients for stratified precise treatment.Many sGC modulators and novel selective PDE inhibitors are now in clinical trials. They are poised to resolve the drawbacks of traditional beta-blockers and RAAS inhibitors — limited efficacy and frequent side effects — and become a leading pipeline for next-generation cardiovascular innovative drugs.

FOR DETAIL:  https://doi.org/10.1098/rstb.2022.0172

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